5-amidino-2-hydroxybenzenesulfonamide derivatives, pharmaceutical compositions containing the same and intermediates for their preparation

ABSTRACT

The present invention relates to a 5-amidino-2-hydroxybenzenesulfonamide derivative represented by the general formula: 
                         
wherein R 1  is a hydrogen atom or an optionally substituted lower alkyl group;
     R 2  is a di(lower alkyl)amino group, a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, or an optionally substituted aromatic heterocyclic group;   T is an oxygen atom, a sulfur atom, a sulfonyl group etc.;   Q is a hydrogen atom or an optionally substituted lower alkyl group; and   Z is a hydrogen atom, a hydroxy group etc.,
 
or a pharmaceutically acceptable salt thereof, which exert a potent and selective activated blood coagulation factor X inhibitory activity and is useful as an agent for the prevention or treatment of a disease occurred associating an activated blood coagulation factor X, a pharmaceutical composition comprising the same, a pharmaceutical use thereof and an intermediate thereof.

TECHNICAL FIELD

The present invention relates to novel5-amidino-2-hydroxybenzenesulfonamide derivatives or pharmaceuticalacceptable salts thereof which are useful as medicaments.

More particularly, the present invention relates to5-amidino-2-hydroxybenzenesulfonamide derivatives or pharmaceuticalacceptable salts thereof, which exert an excellent activated bloodcoagulation factor X inhibitory activity and are useful as activatedblood coagulation factor X inhibitors, pharmaceutical compositionscomprising the same, their pharmaceutical uses and intermediates fortheir preparation.

BACKGROUND ART

The anticoagulation therapy has been extensively performed for theprevention and treatment of thromboembolic diseases caused byaccelerating blood clotting, and drugs such as heparin and warfarinpotassium have been frequently used as anticoagulant agents at present.

However, it has been known that heparin has an antithrombin activity andactivated blood coagulation factor X inhibitory activity and it is aptto cause bleeding tendency.

Warfarin potassium is an anticoagulant which controls biosynthesis ofvitamin K-dependent coagulation factor, and it is difficult to controlthe anticoagulation capacity due to its action mechanism when this drugis used in the prevention and treatment of thromboembolic diseases.Therefore, this drug is extremely difficult to use clinically.

In recent years, selective thrombin inhibitors have been developed andhave been used clinically. However, since thrombin plays a close part inthe conversion of fibrinogen into fibrin in blood coagulation cascadereactions and platelet activation and aggregation, the thrombininhibitors also have similar problems to those of heparin from thesafety point of view such as bleeding tendency and it has been reportedthat their effects are not necessarily enough.

On the other hand, activated blood coagulation factor X, which acts atthe joining point of the extrinsic and intrinsic blood coagulationcascade reactions, locates upstream to thrombin, so that coagulationinhibition is more efficient than that of thrombin inhibitors andtherefore activated blood coagulation factor X inhibitors attract publicattentions as drugs having a possibility that such an inhibition acts tothe coagulation system effectively.

Furthermore, with the changes into European and American life styles andthe increase in aged population in recent years, incidence ofthromboembolic diseases such as myocardial infarction and arteriovenousobstruction will go on increasing, and therefore, demands on developmentof more effective anticoagulants are great and social importance oftheir treatment has been increasing more and more.

DISCLOSURE OF THE INVENTION

The present inventors have studied earnestly to find novel compoundshaving an excellent activated blood coagulation factor X inhibitoryactivity. As a result, it was surprisingly found that certain5-amidino-2-hydroxybenzenesulfonamide derivatives show a potent andselective activated blood coagulation factor X inhibitory activity,thereby forming the basis of the present invention.

The present invention is to provide novel compounds which exert a potentand selective activated blood coagulation factor X inhibitory activity.

This is, the present invention relates to a5-amidino-2-hydroxybenzenesulfonamide derivative represented by thegeneral formula:

wherein R¹ represents a hydrogen atom or a lower alkyl group which mayhave a substituent selected from the following group (A);

-   (A) —COOR^(A), —CONR^(B)R^(C), a 3 to 10-membered cycloalkyl group,    a 6 to 10-membered aryl group, a 3 to 10-membered heterocycloalkyl    group which may have an oxo group, and a 5 to 10-membered aromatic    heterocyclic group which may have an oxo group or a lower alkyl    group;    -   wherein R^(A) represents a hydrogen atom, a 3 to 10-membered        cycloalkyl group or a lower alkyl group which may have a        substituent selected from the following group (i);    -   (i) —COOR^(A1) in which R^(A1) is a hydrogen atom, a 3 to        10-membered cycloalkyl group or a lower alkyl group, —OCOR^(A2)        in which R^(A2) is a 3 to 10-membered cycloalkyl group or a        lower alkyl group, —OCOOR^(A3) in which R^(A3) is a 3 to        10-membered cycloalkyl group or a lower alkyl group, —OR^(A4) in        which R^(A4) is a hydrogen atom, a 3 to 10-membered cycloalkyl        group or a lower alkyl group, —CONR^(A5)R^(A6) in which R^(A5)        and R^(A6) are independently a hydrogen atom or a lower alkyl        group, or —NR^(A5)R^(A6) forms a cyclic amino group, a 3 to        10-membered cycloalkyl group, a 6 to l0-membered aryl group, a 3        to 10-membered heterocycloalkyl group and a 5 to 10-membered        aromatic heterocyclic group;    -   wherein R^(B) and R^(C) independently represent a hydrogen atom        or a lower alkyl group which may have a substituent selected        from the following group (ii), or —NR^(B)R^(C) forms a cyclic        amino group;    -   (ii) —COOR^(B1) in which R^(B1) is a hydrogen atom, a 3 to        10-membered cycloalkyl group or a lower alkyl group,        —CONR^(B2)R^(C2) in which R^(B2) and R^(C2) are independently a        hydrogen atom or a lower alkyl group, or —NR^(B2)R^(C2) forms a        cyclic amino group, a 3 to 10-membered cycloalkyl group, a 6 to        10-membered aryl group, a 3 to 10-membered heterocycloalkyl        group and a 5 to 10-membered aromatic heterocyclic group;-   T represents an oxygen atom, a sulfur atom or a sulfonyl group; or    TR¹ represents —SO₂NR^(B3)R^(C3) in which R^(B3) and R^(C3) are    independently a hydrogen atom or a lower alkyl group;-   R² represents a di( lower alkyl) amino group, a lower alkyl group, a    3 to 10-membered cycloalkyl group, a 6 to 10-membered aryl group    which may have one to three substituents selected from the following    group (B), a 3 to 10-membered heterocycloalkyl group which may have    an oxo group, or a 5 to 10-membered aromatic heterocyclic group    which may have a substituent selected from the following group (C);-   (B) an oxo group, a lower alkyl group, a halo(lower alkyl) group,    —Y—R^(D), a halogen atom, a nitro group, an amino group, —COOR^(E),    a carbamoyl group, a sufamoyl group, a lower alkylsulfonyl group, a    mono(lower alkyl)sulfamoyl group which may have —COOR^(F), and a    lower alkylsulfonylamino-substituted (lower alkyl) group;    -   wherein Y represents an oxygen atom or a sulfur atom;    -   R^(D) represents a hydrogen atom, a halo(lower alkyl) group or a        lower alkyl group which may have —COOR^(D1) in which R^(D1) is a        hydrogen atom, a 3 to 10-membered cycloalkyl group or a lower        alkyl group;    -   R^(E) represents a hydrogen atom, a 3 to 10-membered cycloalkyl        group or a lower alkyl group;    -   R^(F) represents a hydrogen atom, a 3 to 10-membered cycloalkyl        group or a lower alkyl group;-   (C) a lower alkyl group, an amino group and —COOR^(G);    -   wherein R^(G) represents a hydrogen atom, a 3 to 10-membered        cycloalkyl group or a lower alkyl group;-   Q represents a hydrogen atom or a lower alkyl group which may have a    substituent selected from the following group (D);-   (D) —OR^(H), —COOR^(I), —CONR^(J)R^(K), a 6 to 10-membered aryl    group which may have one to three substituents selected from the    following group (iii), and a 5 to 10-membered aromatic heterocyclic    group which may have one to three substituents selected from the    following group (iv);    -   wherein R^(H) represents a hydrogen atom or a lower alkyl group        which may have —OR^(H1) in which R^(H1) is a hydrogen atom or a        lower alkyl group;    -   R^(I) independently has the same meaning as R^(A);    -   R^(J) and R^(K) independently represent a hydrogen atom, a 6 to        10-membered aryl group which may have a carbamoyl group, a 5 to        10-membered aromatic heterocyclic group which may have a        substituent selected from the following group (v), or a lower        alkyl group which may have a substituent selected from the        following group (vi), or —NR^(J)R^(K) forms a cyclic amino group        which may have a substituent selected from the following group        (vii);    -   (v) a halogen atom, a lower alkyl group, a carbamoyl group and        —COOR^(J1) in which R^(J1) is a hydrogen atom or a lower alkyl        group;    -   (vi) —OR^(J2) in which R^(J2) is a hydrogen atom or a lower        alkyl group, and a 5 to 10-membered aromatic heterocyclic group;    -   (vii) a hydroxy group, a lower alkyl group, a hydroxy(lower        alkyl) group, a carbamoyl group, a di(lower alkyl)amino group, a        lower acyl group and —COOR^(J3) in which R^(J3) is a hydrogen        atom or a lower alkyl group;    -   (iii) a halogen atom, a nitro group, a lower alkyl group,        —OR^(L) in which R^(L) is a hydrogen atom or a lower alkyl        group, and —COOR^(M) in which R^(M) is a hydrogen atom or a        lower alkyl group;    -   (iv) a halogen atom, an oxo group, a lower alkyl group and a        phenyl group; and-   Z represents a hydrogen atom, a ydroxyl group or —COOR^(N);-   wherein R^(N) represents a halo(lower alkyl) group, a 6 to    10-membered aryl group, or a lower alkyl group which may have a    substituent selected from the following group (viii);-   (viii) —OR^(N1) in which R^(N1) is a hydrogen atom or a lower alkyl    group, —COOR^(N2) in which R^(N2) is a lower alkyl group which may    have —COOR^(N21) where R^(N21) is a lower alkyl group,    —CONR^(N3)R^(N4) in which R^(N3) and R^(N4) are independently a    hydrogen atom or a lower alkyl group, or —NR^(N3)R^(N4) forms a    cyclic amino group, —OCOR^(N5) in which R^(N5) is a lower alkyl    group which may have —OCOR^(N51) where R^(N51) is a lower alkyl    group, a 3 to 10-membered heterocycloalkyl group and a 6 to    10-membered aryl group;    or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to a5-amidino-2-hydroxybenzenesulfonamide derivative represented by thegeneral formula [I] above or a pharmaceutically acceptable salt thereofwherein Q is a hydrogen atom and Z is not a hydrogen atom.

In still another aspect, the present invention relates to a5-amidino-2-hydroxybenzenesulfonamide derivative as in the proceedingparagraph above wherein Q is a hydrogen atom and Z is not a hydrogenatom or a pharmaceutically acceptable salt thereof:

wherein R¹ is a lower alkyl group having —COOR^(A) wherein R^(A) is ahydrogen atom, a 3 to 10-membered cycloalkyl group or a lower alkylgroup which may have a substituent selected from the following group(i);

-   -   (i) —COOR^(A1) in which R^(A1) is a hydrogen atom, a 3 to        10-membered cycloalkyl group or a lower alkyl group, —OCOR^(A2)        in which R^(A2) is a 3 to 10-membered cycloalkyl group or a        lower alkyl group, —OCOOR^(A3) in which R^(A3) is a 3 to        10-membered cycloalkyl group or a lower alkyl group, —OR^(A4) in        which R^(A4) is a hydrogen atom, a 3 to 10-membered cycloalkyl        group or a lower alkyl group, —CONR^(A5)R^(A6) in which R^(A5)        and R^(A6) are independently a hydrogen atom or a lower alkyl        group, or —NR^(A5)R^(A6) forms a cyclic amino group, a 3 to        10-membered cycloalkyl group, a 6 to 10-membered aryl group, a 3        to 10-membered heterocycloalkyl group and a 5 to 10-membered        aromatic heterocyclic group;        R² is a phenyl group having a substituent selected from the        following group (B);

-   (B) an oxo group, a lower alkyl group, a halo(lower alkyl) group,    —Y-R^(D), a halogen atom, a nitro group, an amino group, —COOR^(E),    a carbamoyl group, a sufamoyl group, a lower alkylsulfonyl group, a    mono(lower alkyl)sulfamoyl group which may have —COOR^(F), and a    lower alkylsulfonylamino-substituted (lower alkyl) group;    -   wherein Y is an oxygen atom or a sulfur atom;    -   R^(D) is a hydrogen atom, a halo(lower alkyl) group or a lower        alkyl group which may have —COOR^(D1) in which R^(D1) is a        hydrogen atom, a 3 to 10-membered cycloalkyl group or a lower        alkyl group;    -   R^(E) is a hydrogen atom, a 3 to 10-membered cycloalkyl group or        a lower alkyl group;    -   R^(F) is a hydrogen atom, a 3 to 10-membered cycloalkyl group or        a lower alkyl group;        T is an oxygen atom; and    -   Z is a hydroxy group.

In still yet a further aspect, the present invention relates to a5-amidino-2-hydroxybenzenesulfonamide derivative as in the proceedingstill another aspect of the present invention or a pharmaceuticallyacceptable salt therof;

wherein R¹ is a methyl group having —COOR^(A10) wherein R^(A10) is a 3to 10-membered cycloalkyl group or a lower alkyl group; and

R² is a phenyl group having a substituent selected from the groupconsisting of a sufamoyl group, a lower alkylsulfonyl group and amono(lower alkyl)sulfamoyl group.

The present invention also relates to a pharmaceutical compositioncomprising as an active ingredient a5-amidino-2-hydroxybenzenesulfonamide derivative represented by theabove general formula (I) or a pharmaceutically acceptable salt thereof.

The present invention relates to an activated blood coagulation factor Xinhibitor comprising as an active ingredient a5-amidino-2-hydroxybenzenesulfonamide derivative represented by theabove general formula (I) or a pharmaceutically acceptable salt thereof.

The present invention relates to an agent for the prevention ortreatment of a disease occurred associating an activated bloodcoagulation factor X, which comprises as an active ingredient a5-amidino-2-hydroxybenzenesulfonamide derivative represented by theabove general formula (I) or a pharmaceutically acceptable salt thereof.

The present invention relates to a method for the prevention ortreatment of a disease occurred associating an activated bloodcoagulation factor X, which comprises administering a therapeuticallyeffective amount of a 5-amidino-2-hydroxybenzenesulfonamide derivativerepresented by the above general formula (I) or a pharmaceuticallyacceptable salt thereof.

The present invention relates to a use of a5-amidino-2-hydroxybenzenesulfonamide derivative represented by theabove general formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a pharmaceutical composition for the preventionor treatment of a disease occurred associating an activated bloodcoagulation factor X.

Furthermore, the present invention relates to a5-cyano-2-hydroxybenzenesulfonamide derivative represented by thegeneral formula:

wherein R¹ represents a hydrogen atom or a lower alkyl group which mayhave a substituent selected from the following group (A);

-   (A) —COOR , —CONR^(B)R^(C), a 3 to 10-membered cycloalkyl group, a 6    to 10-membered aryl group, a 3 to 10-membered heterocycloalkyl group    which may have an oxo group, and a 5 to 10-membered aromatic    heterocyclic group which may have an oxo group or a lower alkyl    group;    -   wherein R^(A) represents a hydrogen atom, a 3 to 10-membered        cycloalkyl group or a lower alkyl group which may have a        substituent selected from the following group (i);    -   (i) —COOR^(A1) in which R^(A1) is a hydrogen atom, a 3 to        10-membered cycloalkyl group or a lower alkyl group, —OCOR^(A2)        in which R^(A2) is a 3 to 10-membered cycloalkyl group or a        lower alkyl group, —OCOOR^(A3) in which R^(A3) is a 3 to        10-membered cycloalkyl group or a lower alkyl group, —OR^(A4) in        which R^(A4) is a hydrogen atom, a 3 to 10-membered cycloalkyl        group or a lower alkyl group, —CONR^(A5)R^(A6) in which R^(A5)        and R^(A6) are independently a hydrogen atom or a lower alkyl        group, or —NR^(A5)R^(A6) forms a cyclic amino group, a 3 to        10-membered cycloalkyl group, a 6 to 10-membered aryl group, a 3        to 10-membered heterocycloalkyl group and a 5 to 10-membered        aromatic heterocyclic group;    -   wherein R^(B) and R^(C) independently represent a hydrogen atom        or a lower alkyl group which may have a substituent selected        from the following group (ii), or —NR^(B)R^(C) forms a cyclic        amino group;    -   (ii) —COOR^(B1) in which R^(B1) is a hydrogen atom, a 3 to        10-membered cycloalkyl group or a lower alkyl group,        —CONR^(B2)R^(C2) in which R^(B2) and R^(C2) are independently a        hydrogen atom or a lower alkyl group, or —NR^(B2)R^(C2) forms a        cyclic amino group, a 3 to 10-membered cycloalkyl group, a 6 to        10-membered aryl group, a 3 to 10-membered heterocycloalkyl        group and a 5 to 10-membered aromatic heterocyclic group;-   T represents an oxygen atom, a sulfur atom or a sulfonyl group; or    TR¹ represents—SO₂NR^(B3)R^(C3) in which R^(B3) and R^(C3) are    independently a hydrogen atom or a lower alkyl group;-   R² represents a di(lower alkyl)amino group, a lower alkyl group, a 3    to 10-membered cycloalkyl group, a 6 to 10-membered aryl group which    may have one to three substituents selected from the following group    (B), a 3 to 1 0-membered heterocycloalkyl group which may have an    oxo group, or a 5 to 10-membered aromatic heterocyclic group which    may have a substituent selected from the following group (C);-   (B) an oxo group, a lower alkyl group, a halo(lower alkyl) group,    —Y—R^(D), a halogen atom, a nitro group, an amino group, —COOR^(E),    a carbamoyl group, a sufamoyl group, a lower alkylsulfonyl group, a    mono(lower alkyl)sulfamoyl group which may have —COOR^(F), and a    lower alkylsulfonylamino-substituted (lower alkyl) group;    -   wherein Y represents an oxygen atom or a sulfur atom;    -   R^(D) represents a hydrogen atom, a halo(lower alkyl) group or a        lower alkyl group which may have —COOR^(D1) in which R^(D1) is a        hydrogen atom, a 3 to 10-membered cycloalkyl group or a lower        alkyl group;    -   R^(E) represents a hydrogen atom, a 3 to 1 0-membered cycloalkyl        group or a lower alkyl group;    -   R^(F) represents a hydrogen atom, a 3 to 10-membered cycloalkyl        group or a lower alkyl group;-   (C) a lower alkyl group, an amino group and —COOR^(G);    -   wherein R^(G) represents a hydrogen atom, a 3 to 10-membered        cycloalkyl group or a lower alkyl group;-   Q represents a hydrogen atom or a lower alkyl group which may have a    substituent selected from the following group (D);-   (D) —OR^(H), —COOR^(I), —CONR^(J)R^(K), a 6 to 10-membered aryl    group which may have one to three substituents selected from the    following group (iii), and a 5 to 10-membered aromatic heterocyclic    group which may have one to three substituents selected from the    following group (iv);-   wherein R^(H) represents a hydrogen atom or a lower alkyl group    which may have —OR^(H1) in which R^(H1) is a hydrogen atom or a    lower alkyl group;-   R^(I) independently has the same meaning as R^(A);-   R^(J) and R^(K) independently represent a hydrogen atom, a 6 to    10-membered aryl group which may have a carbamoyl group, a 5 to    10-membered aromatic heterocyclic group which may have a substituent    selected from the following group (v), or a lower alkyl group which    may have a substituent selected from the following group (vi), or    —NR^(J)R^(K) forms a cyclic amino group which may have a substituent    selected from the following group (vii);-   (v) a halogen atom, a lower alkyl group, a carbamoyl group and    —COOR^(J1) in which R^(J1) is a hydrogen atom or a lower alkyl    group;-   (vi) —OR^(J2) in which R^(J2) is a hydrogen atom or a lower alkyl    group, and a 5 to 10-membered aromatic heterocyclic group;-   (vii) a hydroxy group, a lower alkyl group, a hydroxy(lower alkyl)    group, a carbamoyl group, a di(lower alkyl)amino group, a lower acyl    group and —COOR^(J3) in which R^(J3) is a hydrogen atom or a lower    alkyl group;    -   (iii) a halogen atom, a nitro group, a lower alkyl group,        —OR^(L) in which R^(L) is a hydrogen atom or a lower alkyl        group, and —COOR^(M) in which R^(M) is a hydrogen atom or a        lower alkyl group; and    -   (iv) a halogen atom, an oxo group, a lower alkyl group and a        phenyl group;        or a salt thereof.

In the present invention, the term “lower alkyl group” means astraight-chained or branched alkyl group having 1 to 6 carbon atoms suchas a methyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a sec-butyl group, a pentyl group, anisopentyl group, a neopentyl group, a 1-methylbutyl group, a2-methylbutyl group, a hexyl group or the like. The term “loweralkylsulfonyl group” means a sulfonyl group having the above lower alkylgroup, such as a methanesulfonyl group, an ethanesulfonyl group, apropanesulfonyl group, an isopropanesulfonyl group, a butanesulfonylgroup, an isobutanesulfonyl group, a sec-butanesulfonyl group, apentanesulfonyl group, an isopentanesulfonyl group, a neopentanesulfonylgroup, a hexanesulfonyl group or the like. The term “mono(loweralkyl)sulfamoyl group” means a monoalkyl-sulfamoyl group wherein thealkyl moiety is the same as the above lower alkyl group. The term“di(lower alkyl)amino group” means an amino group di-substituted by sameor different lower alkyl groups as defined above. The term “loweralkylsulfonyl-amino-substituted (lower alkyl) group” means the abovealkyl group having an amino group N-substituted by the above loweralkylsulfonyl group. The term “hydroxy(lower alkyl) group” means astraight-chained or branched alkyl group having 2 to 6 carbon atoms andsubstituted by a hydroxy group. The term “lower acyl group” means astraight-chained or branched alkoxycarbonyl group having 2 to 6 carbonatoms such as an acetyl group, a propionyl group, a butyryl group, anisobutyryl group, a valeryl group, a hexanoyl group or the like. Theterm “lower alkylene group” means a straight-chained or branchedalkylene group having 1 to 6 carbon atoms such as a methylene group, anethylene group, a trimethylene group, a propylene group or the like.

The term “3 to 10-membered cycloalkyl group” means a 3 to 7-memberedmonocyclic aliphatic alkyl group such as a cyclopropyl group, acyclobutyl group, a cyclopentyl group, a cyclohexyl group or acycloheptyl group, or a cyclopentyl group or a cyclohexyl group whichare fused with a benzene ring. The term “6 to 10-membered aryl group”means a phenyl group, a naphthyl group, or a phenyl group which is fusedwith a cyclopentane ring or a cyclohexane ring.

The term “3 to 10-membered heterocycloalkyl group” means a 3 to7-membered monocyclic heteroalkyl group containing one to two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom inthe ring, or a bicyclic heteroalkyl group which is benzene-fused 5 or6-membered monocyclic heteroalkyl group as defined above, and asexamples of such groups, for example, a monovalent group derived frommorpholine, thiomorpholine, pyrrolidine, imidazoline, oxazoline,piperidine, piperazine, tetrahydrofuran, aziridine, azetidine, indoline,isoindoline, chroman, isochroman or the like can be illustrated. Asexamples of heterocycloalkyl group having an oxo group, for example, amonovalent group derived from a 2-oxazolidone or the like.

The term “5 to 10-membered aromatic heterocyclic group” means a 5 to6-membered monocyclic aromatic group containing one to four hetero atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom in thering, or a bicyclic heteroalkyl group which is benzene or pyridine-fused5 or 6-membered monocyclic aromatic group as defined above, and asexamples of such groups, for example, a monovalent group derived frompyridine, pyrimidine, pyrazine, pyridazine, pyrrole, thiophene, oxazole,thiazole, imidazole, pyrazole, oxadiazole, thiodiazole, tetrazole,indole, indolizine, benzofuran, benzothiophene, quinoline, isoquinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline or thelike can be illustrated. As examples of aromatic heterocyclic grouphaving an oxo group, for example, a monovalent group derived from a1,3,4-oxadiazol-2-one or the like can be illustrated.

The term “cyclic amino group” means a 5 to 6-membered monocyclic aminogroup which may contain one hetero atom selected from a nitrogen atom,an oxygen atom and a sulfur atom other than the nitrogen atom at thebinding site in the ring, such as a 1-pyrrolodinyl group, a piperidinogroup, a morpholino group, a thiomorpholino group, a 1-piperazinyl groupor the like.

The term “halogen atom” means a fluorine atom, a chlorine atom, abromine atom or an iodine atom. The term “halo(lower alkyl) group” meansthe above alkyl group substituted by one to three halogen atom asdefined above, such as a trifluoromethyl group, a 2,2,2-trifluoroethylgroup or the like.

The term “hydroxy-protective group” means a hydroxy-protective groupused generally in organic synthesis, which is described in PROTECTIVEGROUPS IN ORGANIC SYNTHESIS, THEODORA W. GREENE, PETER G. WUTS by JOHNWILEY&SONS, INC, such as a benzyl group, a methoxymethyl group, anacetyl group or the like.

For example, the compounds represented by the above general formula (I)of the present invention can be prepared by allowing a5-cyano-2-hydroxybenzenesulfonamide derivative represented by the abovegeneral formula (II) or a salt thereof to react with an alcohol in thepresence of hydrogen chloride (hereinafter referred to as Process 1),allowing the resulting compound to react with ammonia or a salt thereof,or hydroxylamine or a salt thereof (hereinafter referred to as Process2), carrying out, as occasion demands, suitably one to four processesselected from the group consisting of (1) hydrolysis of the resultingester group (hereinafter referred to as Process 3), (2) esterinterchange or esterification of the resulting compound using an alcoholcompound represented by the general formula:R^(A)—OH  [III]wherein R^(A) has the same meaning as defined above, or esterificationof the resulting compound using a compound represented by the generalformula:R^(A)—X¹  [IV]wherein X¹ represents a leaving group such as a halogen atom, atoluenesulfonyloxy group, a methanesulfonyloxy group or the like; andR^(A) has the same meaning as defined above (hereinafter referred to asProcess 4), (3) introduction of a protective group into a phenolichydroxy group (hereinafter referred to as Process 5) and (4) N-acylationof the resulting compound using a compound represented by the generalformula:R^(N)OCO—X²  [V]wherein X² represents a leaving group such as a halogen atom, a4-nitrophenoxy group or the like; and R^(N) has the same meaning asdefined above, and subjecting, as occasion demands, to removal of theprotective group of the phenolic hydroxy group or O-deacylation in theusual way.

In the aforementioned production process, the reaction from a5-cyano-2-hydroxybenzenesulfonamide derivative represented by the abovegeneral formula (II) into a 5-amidino-2-hydroxybenzenesulfonamidederivative represented by the above general formula (I) is as follows indetail.

Process 1

A corresponding imidate compound can be prepared by allowing a5-cyano-2-hydroxybenzenesulfonamide derivative represented by the abovegeneral formula (II) to react with an alcohol such as methanol orethanol in the presence of a hydrogen halide such as hydrogen chlorideor hydrogen bromide at usually −20° C. to room temperature. As a solventused, methanol, ethanol, a mixed solvent of such alcohol withtetrahydrofuran, dichloromethane or N,N-dimethylformamide, and the likecan be illustrated. The reaction time is usually from 1 hour to 3 days,varying based on sorts and volumes of a used starting material andsolvent.

Process 2

A corresponding amidino compound can be prepared by allowing an imidatecompound to react with ammonia or an ammonium salt such as ammoniumcarbonate, ammonium chloride or ammonium acetate, or hydroxylamine or asalt thereof in the presence or absence of a base such as triethylamineat usually 0° C. to room temperature. As a solvent used, methanol,ethanol, tetra-hydrofuran, dichloromethane and the like can beillustrated. The reaction time is usually from 1 hour to 3 days, varyingbased on sorts and volumes of a used starting material and solvent.

Process 3

In case of compounds having an ester group in the amidino derivativesobtained by Process 2, a corresponding carboxylic acid compound can beprepared by subjecting such compound to hydrolysis using an acid such ashydrochloric acid or sulfuric acid at usually room temperature to refluxtemperature, or a base such as sodium hydroxide at usually 0° C. toreflux temperature. As a solvent used, water, acetonitrile,tetrahydrofuran, alcohols, a mixed solvent thereof and the like can beillustrated. The reaction time is usually from 1 hour to 2 days, varyingbased on sorts and volumes of a used starting material and solvent.

Process 4

A corresponding ester compound can be prepared by 1) subjecting anamidino derivative having an ester group or a carboxy group obtained byProcess 2 or 3 to ester interchange or esterification using an alcoholcompound represented by the above general formula (III) in the presenceof an acid such as hydrochloric acid, sulfuric acid or p-toluenesulfonicacid at usually 0° C. to reflux temperature, by 2) subjecting a compoundhaving a carboxy group of the amidino derivatives obtained by Process 2or 3 to esterification using an alcohol compound represented by theabove general formula (III) in the presence of a condensing agent suchas 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride atusually 0° C. to reflux temperature, or by 3) subjecting a compoundhaving a carboxy group of the amidino derivatives obtained by Process 2or 3 to esterification using a compound represented by the above generalformula (IV) in the presence of a base such as potassium carbonate ortriethylamine, or silver carbonate at usually 0° C. to refluxtemperature. As a solvent used, an aprotic solvent such astetrahydrofuran and the like can be illustrated. The reaction time isusually from 1 hour to 2 days, varying based on sorts and volumes of aused starting material and solvent.

Process 5

A corresponding O-protected compound can be prepared by suitablyprotecting a phenolic hydroxy group of a compound having an amidinogroup obtained by Processes 2–4 according to a method described inPROTECTIVE GROUPS IN ORGANIC SYNTHESIS, THEODORA W. GREENE, PETER G.WUTS by JOHN WILEY&SONS, INC.

Process 6

A corresponding carbamate compound can be prepared by allowing acompound having an amidino group obtained by Processes 2–5 to react witha compound represented by the above general formula (V) in the presenceor absence of a base such as triethylamine or diisopropylethylamine atusually 0° C. to room temperature. As a solvent used,N,N-dimethylformamide and the like can be illustrated. The reaction timeis usually from 1 hour to 2 days, varying based on sorts and volumes ofa used starting material and solvent.

The removal of the protective group of the hydroxy group can be commonlycarried out according to a method described in PROTECTIVE GROUPSINORGANIC SYNTHESIS, THEODORA W. GREENE, PETER G. WUTS by JOHNWILEY&SONS, INC.

Of the compounds represented by the above general formula (I) of thepresent invention, a compound represented by the general formula:

wherein Q, R¹, R² and T have the same meanings as defined above, can bealso prepared by allowing a 5-cyano-2-hydroxy-benzenesulfonamidederivative represented by the above general formula (II) or a saltthereof to react with hydroxylamine or a salt thereof in the presence orabsence of a base (hereinafter referred to as Process 9), andsubjecting, as occasion demands, the resulting compound to esterinterchange or esterification using an alcohol compound represented bythe above general formula (III), or to esterification using a compoundrepresented by the above general formula (IV) (hereinafter referred toas Process 10). In case that 5-cyano-2-hydroxybenzenesulfonamidederivatives represented by the above general formula (II) as startingmaterials have a carboxy group, it is preferable that Process 9 iscarried out after converting it into an inorganic salt of acorresponding carboxylic acid (e.g. a sodium salt, a potassium salt)(hereinafter referred to as Process 8). In case that5-cyano-2-hydroxybenzenesulfonamide derivatives represented by the abovegeneral formula (II) as starting materials have an ester group, it ispreferable that Process 9 is carried out after hydrolysis of the estergroup (hereinafter referred to as Process 7) and Process 8.

In the aforementioned production process, the reaction from a5-cyano-2-hydroxybenzenesulfonamide derivative represented by the abovegeneral formula (II) into a 5-amidino-2-hydroxybenzenesulfonamidederivative represented by the above general formula (Ia) is as followsin detail.

Process 7

A corresponding carboxylic acid compound can be prepared by subjecting acorresponding 5-cyano-2-hydroxybenzene-sulfonamide derivative having anester group to hydrolysis using an acid such as hydrochloric acid orsulfuric acid at usually room temperature to reflux temperature, orusing a base such as sodium hydroxide at usually 0° C. to refluxtemperature. As a solvent used, water, acetonitrile, tetrahydrofuran,alcohols, a mixed solvent thereof and the like can be illustrated. Thereaction time is usually from 1 hour to 2 days, varying based on sortsand volumes of a used starting material and solvent.

Process 8

A corresponding 5-cyano-2-hydroxybenzenesulfonamide derivative having acarboxy group can be converted by treating with a base such as sodiumhydroxide or potassium hydroxide in the presence of various solvents orwithout any solvent at usually −20° C. to room temperature into acorresponding inorganic salt of the carboxylic acid compound. As asolvent used, water, ethanol, tetrahydrofuran, a mixed solvent thereofand the like can be illustrated. The reaction time is usually from 1hour to 2 days, varying based on sorts and volumes of a used startingmaterial and solvent.

Process 9

A corresponding amidoxime compound can be prepared by allowing a5-cyano-2-hydroxybenzenesulfonamide derivative represented by the abovegeneral formula (II), which is obtained by treating according toProcesses 7 and 8 as occasion demands, to react with hydroxylamine or asalt thereof in the presence or absence of a base such as triethylamineat usually 50° C. to reflux temperature. As a solvent used, water,methanol, ethanol, tetrahydrofuran, toluene, a mixed solvent thereof andthe like can be illustrated. The reaction time is usually from 1 hour to3 days, varying based on sorts and volumes of a used starting materialand solvent.

Process 10

A corresponding ester compound can be prepared by 1) subjecting anamidoxime compound having an ester group or a carboxy group obtained byProcess 9 to ester interchange or esterification using an alcoholcompound represented by the above general formula (III) in the presenceof an acid such as hydrochloric acid, sulfuric acid or p-toluenesulfonicacid at usually 0° C. to reflux temperature, by 2) subjecting anamidoxime derivative having a carboxy group obtained by Process 9 toesterification using an alcohol compound represented by the abovegeneral formula (III) in the presence of a condensing agent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at usually0° C. to reflux temperature, or by 3) subjecting an amidino derivativehaving a carboxy group obtained by Process 9 to esterification using acompound represented by the above general formula (IV) in the presenceof a base such as potassium carbonate or triethylamine, or silvercarbonate at usually 0° C. to reflux temperature. As a solvent used, anaprotic solvent such as tetrahydrofuran and the like can be illustrated.The reaction time is usually from 1 hour to 2 days, varying based onsorts and volumes of a used starting material and solvent.

Of the compounds represented by the above general formula (I), acompound represented by the general formula:

wherein R³ represents —COOR^(A7) in which R^(A7) is a lower alkyl grouphaving —CONR^(A5)R^(A6) where R^(A5) and R^(A6), or —NR^(A5)R^(A6) havethe same meanings as defined above, or a lower alkyl group having—CONR^(B)R^(C) where R^(B) and R^(C), or —NR^(B)R^(C) have the samemeanings as defined above; and R², Q, T and Z have the same meanings asdefined above, can be prepared by allowing a compound represented by thegeneral formula:

wherein R⁴ represents —COOR^(A8) in which R^(A8) is a hydrogen atom or alower alkyl group having —COOH; and R², Q, T and Z have the samemeanings as defined above, or a salt thereof to react with an aminecompound represented by the general formula:HNR^(A5)R^(A6)  [VI]wherein R^(A5) and R^(A6), or —NR^(A5)R^(A6) have the same meanings asdefined above, or a salt thereof, or an amine compound represented bythe general formula:HNR^(B)R^(C)  [VII]wherein R^(A5) and R^(A6), or —NR^(A5)R^(A6) have the same meanings asdefined above, or a salt thereof (hereinafter referred to as Process11).

In the aforementioned production process, the reaction from a5-amidino-2-hydroxybenzenesulfonamide derivative represented by theabove general formula (Ic) into a 5-amidino-2-hydroxybenzenesulfonamidederivative represented by the above general formula (Ib) is as followsin detail.

Process 11

A 5-amidino2-hydroxybenzenesulfonamide derivative represented by theabove general formula (Ib) can be prepared by allowing a5-amidino-2-hydroxybenzenesulfonamide derivative represented by theabove general formula (Ic) or a salt thereof to react with an aminecompound represented by the above general formula (VI) or a saltthereof, or an amine compound represented by the above general formula(VII) or a salt thereof in the presence of a condensing agent such as1-(3-dimethylaminoproyl) -3-ethyl-carbodiimide hydrochloride,diphenylphoshoryl azide or the like and in the presence or absence of anagent for making an activated ester such as 1-hydroxybenzotriazolemonohydrate and a base such as triethylamine at usually 0° C. to roomtemperature. As a solvent used, dichloromethane, N,N-dimethylformamideand the like can be illustrated. The reaction time is usually from 1hour to 2 days, varying based on sorts and volumes of a used startingmaterial and solvent.

For example, the 5-cyano-2-hydroxybenzenesulfonamide derivativesrepresented by the above general formula (II) used as starting materialsin the aforementioned production processes can be prepared by thefollowing method:

wherein R⁵ represents a lower alkyl group which may have a substituentselected from the following group (A);

-   (A) —COOR^(A), —CONR^(B)R^(C), a 3 to 10-membered cycloalkyl group,    a 6 to 10-membered aryl group, a 3 to 10-membered heterocycloalkyl    group which may have an oxo group, and a 5 to 10-membered aromatic    heterocyclic group which may have an oxo group or a lower alkyl    group;    -   wherein R^(A), R^(B) and R^(C), or —NR^(B)R^(C) have the same        meanings as defined above;-   R⁶ represents a halogen atom, a ydroxyl group, a di(lower    alkyl)amino group, a lower alkyl group, a 3 to 10-membered    cycloalkyl group, or a 3 to 10-membered heterocycloalkyl group which    may have an oxo group;-   R⁷ represents a 5 to 10-membered aromatic heterocyclic group which    may have a substituent selected from the following group (C), or a 6    to 10-membered aryl group which may have one to three substituents    selected from the following group (E);-   (C) a lower alkyl group, an amino group and —COOR^(G) in which R^(G)    has the same meaning as defined above;-   (E) an oxo group, a lower alkyl group, a halo(lower alkyl) group,    —Y—R^(D), a halogen atom, a nitro group, an amino group, —COOR^(E),    a carbamoyl group, a sufamoyl group, a mono(lower alkyl)sulfamoyl    group which may have —COOR^(F), and a lower    alkylsulfonylamino-substituted (lower alkyl) group;    -   wherein R^(D), R^(E), R^(F) and Y have the same meanings as        defined above-   R⁸ represents a hydrogen atom or a lower alkyl group, or both of R⁸    bind to form a lower alkylene group;-   Q¹ represents a lower alkyl group which may have a substituent    selected from the following group (D);-   (D) —OR^(H), —COOR^(I), —CONR^(J)R^(K), a 6 to 10-membered aryl    group which may have one to three substituents selected from the    following group (iii), and a 5 to 10-membered aromatic heterocyclic    group which may have one to three substituents selected from the    following group (iv);    -   wherein R^(H), R^(I), R^(J) and R^(K), or —NR^(J)R^(K) have the        same meanings as defined above;    -   (iii) a halogen atom, a nitro group, a lower alkyl group,        —OR^(L) in which R^(L) has the same meaning as defined above,        and —COOR^(M) in which R^(M) has the same meaning as defined        above;    -   (iv) a halogen atom, an oxo group, a lower alkyl group and a        phenyl group; and-   T¹ represents an oxygen atom or a sulfur atom;-   X³ represents a chlorine atom, a bromine atom or an iodine atom;-   X⁴ represents a chlorine atom, a bromine atom or an iodine atom; and-   Q, R¹, R² and T have the same meanings as defined above.    Process A

A benzenesulfonamide derivative represented by the above general formula(X) can be prepared by condensing a benzene-sulfonyl halide derivativerepresented by the above general formula (VIII) with a phenethylaminederivative represented by the above general formula (IX) or a saltthereof in the presence or absence of a base such as triethylamine orpotassium carbonate in a polar solvent such as tetrahydrofuran,N,N-dimethyl-formamide, or a mixed solvent of such solvent with water atusually 0° C. to room temperature.

Process B

A benzenesulfonamide derivative represented by the above general formula(XII) can be prepared by condensing a benzene-sulfonamide derivativewherein R⁶ is a hydroxy group represented by the above general formula(X) with a trifluoromethanesulfonic anhydride represented by the abovegeneral formula (XI) in the presence of a base such asN,N-dimethylaminopyridine in a solvent such as dichloromethane,tetrahydrofuran at usually 0° C. to reflux temperature.

Process C

A benzenesulfonamide derivative represented by the above general formula(XIV) can be prepared by condensing a benzene-sulfonamide derivativerepresented by the above general formula (XII) or a benzenesulfonamidederivative wherein R⁶ is a halogen atom represented by the above generalformula (X) with a boron compound represented by the above generalformula (XIII) in the presence of a catalyst such astetrakis(triphenylphosphine)palladium(0), palladium(II) acetate or[1,1′-bis(diphenylphosphino)ferrocene]chloronickel(II) and a base suchas sodium carbonate, sodium hydrogen carbonate, potassium phosphate ortriethylamine and in the presence or absence of a phase-transfercatalyst such as tetrabutylammonium bromide in a solvent such astoluene, tatrahydrofuran, N,N-dimethyl-formamide or water, or a mixedsolvent thereof at usually room temperature to reflux temperature.

Process D

A compound wherein R⁷ is a (lower alkyl)thioaryl group and/or T is asulfur atom of a compound represented by the above general formula (XIV)can be converted into a corresponding sulfonyl compound by treating itwith an oxidizing agent such as oxone (trademark) or m-chloroperbenzoicacid in a solvent such as acetone or dichloromethane, or a mixed solventof such solvent with water at usually 0° C. to reflux temperature.

Process E

A compound of the above general formula (X) or (XIV), or a compoundwherein T¹ is an oxygen atom and R⁵ is a benzyl group of a compoundwherein R⁷ is a (lower alkyl)thioaryl group oxidizing the sulfur atomrepresented by the above general formula (XIV) can be converted into acorresponding phenol compound represented by the above general formula(XV) by subjecting it to catalytic hydrogenation using a palladiumcatalyst such as palladium-carbon or palladium hydroxide in a hydrogenatmosphere in a polar solvent such as ethanol at usually roomtemperature to reflux temperature and at atmospheric pressure or appliedpressure to remove the benzyl group. This process can be similarlycarried out using a compound wherein T¹ or T is an oxygen atom and R¹ isa benzyl group after the following Process F or G.

Process F

A corresponding N-alkylated compound can be prepared by subjecting acompound represented by the above general formula (XV) to N-alkylationusing an alkylating agent represented by the above general formula (XVI)in the presence of a base such as triethylamine or potassium carbonatein a solvent such as N,N-dimethylformamide at usually −20° C. to refluxtemperature.

Process G

A benzenesulfonamide derivative represented by the above general formula(II) can be prepared by subjecting a compound of the above generalformula (XV) or a compound N-alkylated by Process F to demethylationunder heating in the presence of lithium chloride in a solvent such asN,N-dimethylformamide or N,N-dimethylacetamide at usually 100° C. toreflux temperature.

For example, of a compound represented by the above general formula (XV)in the aforementioned production process, a compound wherein R¹ has anamide group represented by the following general formula (XVb) can bealso prepared by the following method:

wherein R⁹ represents a lower alkyl group having a substituent selectedfrom the following group (F);

-   (F) —COOR^(A9) or —CONR^(B4)R^(C4);    -   wherein R represents a lower alkyl group;    -   R^(B4) and R^(C4) independently represent a hydrogen atom or a        lower alkyl group having —COOR^(B5) in which R^(B5) is a lower        alkyl group, with the proviso that both are not a hydrogen atom;-   R¹⁰ represents a lower alkyl group having a substituent selected    from the following group (G);-   (G) —COOH or —CONR^(B6)R^(C6);    -   wherein R^(B6) and R^(C6) independently represent a hydrogen        atom or a lower alkyl group having —COOH, with the proviso that        both are not a hydrogen atom; and-   R², R³, R^(A5), R^(A6), R^(B) and R^(C), —NR^(B)R^(C) and T have the    same meanings as defined above.    Process H

A compound represented by the above general formula (XVI) can behydrolyzed into a corresponding carboxylic acid compound represented bythe above general formula (XVa) by treating it with an acid such ashydrochloric acid or sulfuric acid at room temperature to ref luxtemperature, or with a base such as sodium hydroxide in water and asolvent such as acetonitrile, tetrahydrofuran or alcohols at usually 0°C. to reflux temperature.

Process I

A compound represented by the above general formula (XVa) can beconverted into a corresponding amide compound represented by the abovegeneral formula (XVb) by allowing it to react with an amine compoundrepresented by the above general formula (VI) or a salt thereof, or anamine compound represented by the above general formula (VII) or a saltthereof in the presence of a condensing agent such as1-(3-dimethylaminoproyl)-3-ethyl-carbodiimide hydrochloride ordiphenylphoshoryl azide and in the presence or absence of an agent formaking an activated ester such as 1-hydroxybenzotriazole monohydrate anda base such as triethylamine in a solvent such as dichloromethane orN,N-dimethylformamide at usually 0° C. to room temperature.

In the aforementioned production process, for example, a compoundrepresented by the above general formula (XIV) can be also prepared bythe following method:

wherein X⁵ represents a bromine atom, a chlorine atom or an iodine atom;and

-   R⁵, R⁷ and T¹ have the same meanings as defined above.    Process J

A benzenesulfonamide derivative represented by the above general formula(XIV) can be prepared by condensing a benzenesulfonamide derivativerepresented by the above general formula (XII) with a halide compoundrepresented by the above general formula (XVII) in the presence of aborate such as bis(pinacolato)diboron and a catalyst such as[1,1′-bis-(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane complex a in a solvent such as dioxane at usually roomtemperature to reflux temperature.

For example, the compound represented by the above general formula (XV)in the aforementioned production process can be also prepared using acompound represented by the following general formula (XVIII) obtainedby a similar reaction according to the above Processes A, B, C and Jfrom a corresponding compound wherein R⁵ is a methoxymethyl grouprepresented by the above general formula (IX) as a starting material bythe following method:

wherein X⁶ represents a bromine atom, a chlorine atom or an iodine atom;and

-   R¹, R², R⁵, T and T¹ have the same meanings as defined above.    Process K

A compound represented by the above general formula (XVIII) can beconverted into a phenol compound or a thiophenol compound represented bythe above general formula (XVc) by treating it in the presence of anacid such as hydrochloric acid or sulfuric acid in a solvent such astetrahydrofuran or isopropanol, or a mixed solvent thereof at usually 0°C. to reflux temperature.

Process L

A corresponding O- or S-alkylated compound represented by the abovegeneral formula (XVd) can be prepared by condensing a compoundrepresented by the above general formula (XVc) with a halide compoundrepresented by the above general formula (XIX) in the presence of a basesuch as N,N-diisopropylethylamine, triethylamine or potassium carbonatea in a solvent such as N,N-dimethylformamide, tetrahydrofuran or ethanolat usually −20° C. to reflux temperature.

Process M

A compound wherein T¹ is a sulfur atom and R¹ is not a hydrogen atom ofa compound represented by the above general formula (XVd) can beconverted into a corresponding sulfonyl compound by treating it with anoxidizing agent such as oxone (trademark) or m-chloroperbenzoic acid ina solvent such as acetone or dichloromethane, or a mixed solvent of suchsolvent with water at usually 0° C. to reflux temperature.

For example, the compound represented by the above general formula (V)in the aforementioned production process is commercially available orcan be prepared by methods described in literature or the like (MichaelFolkmann, Synthesis, 1159 (1990); Jose Alxander, J. Med. Chem., 318–322,31 (1988)).

The compounds of the present invention obtained by the above productionprocess can be easily isolated and purified by conventional separationmeans such as fractional recrystallization, precipitation, purificationusing column chromatography, solvent extraction and the like.

The 5-amidino-2-hydroxybenzenesulfonamide derivatives represented by theabove general formula (I) of the present invention can be converted intotheir pharmaceutically acceptable salts in the usual way. Examples ofthe such salts include acid addition salts with mineral acids (e.g.,hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, phosphoric acid and the like), acid addition salts withorganic acids (e.g., formic acid, acetic acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citricacid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalicacid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid,glutamic acid, aspartic acid and the like), salts with organic amines(e.g., morpholine, pyrrolidine, piperidine, piperazine, lysine and thelike), and salts with inorganic bases such as a sodium salt, a potassiumsalt and a calcium salt.

In addition, the compounds represented by the above general formula (I)of the present invention also include its hydrates and solvates withpharmaceutically acceptable solvents (e.g., ethanol).

Of the compounds represented by the above general formula (I) of thepresent invention, compounds having an asymmetric carbon atom exist intwo optical isomer forms of (R) configuration and (S) configuration.Either one of the isomers or a mixture thereof can be employed in thepresent invention. In the compounds represented by the above generalformula (I) of the present invention, when geometrical isomers ortautomers exist, the present invention includes all of the geometricalisomers and tautomers.

The compounds represented by the above general formula (I) of thepresent invention are compounds having a potent inhibitory activity onactivated blood coagulation factor X and anti-coagulation activity. Thecompounds represented by the above general formula (I) of the presentinvention also have an extremely weak inhibitory activity on thrombinand therefore are highly selective activated blood coagulation factor Xinhibitors.

Furthermore, in the compounds represented by the above general formula(I) of the present invention, the substituent R¹ is preferably a loweralkyl group having —COOR^(A) wherein R^(A) has the same meaning asdefined above, and more preferably a methyl group having —COOR^(A10)wherein R^(A10) is a 3 to 10-membered cycloalkyl group or a lower alkylgroup. The substituent R² is preferably a phenyl group having asubstituent selected from the above group (B), and the substituent ispreferably at the p-position. Furthermore, the substituent R² is morepreferably a phenyl group having a substituent selected from the groupconsisting of a sulfamoyl group, a lower alkylsulfonyl group and amono(lower alkyl)sulfamoyl group, and most preferably a phenyl grouphaving a lower alkylsulfonyl group. The substituent Q is preferably ahydrogen atom. The substituent T is preferably an oxygen atom. Thesubstituent Z is preferably a hydroxy group or —COOR^(N) wherein R^(N)has the same meaning as defined above, and more preferably a hydroxygroup. Compounds having such the substituent Z and pharmaceuticallyacceptable salts thereof are excellent compounds which can exert afavorable activated blood coagulation factor X inhibitory activity whenthey are orally administered. As the compounds represented by the abovegeneral formula (I) of the present invention, ethyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonyl-amino]ethyl]-2′-mthanesulfonylbiphenyl-3-yloxy]acetate,isopropyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate,n-butyl[4-[2-[2-hydroxy-5-(N-hydroxy-carbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetateandcyclohexyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]-ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetateare preferable, andisopropyl[4-[2-[2-hydroxy-5-(N-hydroxy-carbamimidoyl)benzenesulfonylamino]ethyl]-2′-methane-sulfonylbiphenyl-3-yloxy]acetate,n-butyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetateand cyclohexyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonyl-amino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetateare more preferable.

The compounds represented by the above general formula (I) of thepresent invention are selective activated blood coagulation factor Xinhibitors. In consequence, the compounds of the present invention areextremely useful as agents for the prevention or treatment of cerebralinfarction, cerebral thrombosis, cerebral embolism, transient cerebralischemic attack (TIA), subarachnoid hemorrhage-induced cerebralvasospasm, alzheimer's disease, myocardial infarction, unstable angina,heart failure, atrial fibrillary thrombosis, pulmonary thrombosis,pulmonary embolism, acute respiratory distress syndrome, Berger disease,peripheral arterial obstruction, deep venous thrombosis, disseminatedintravascular coagulation syndrome, atherosclerosis, behcet's disease,diabetic neuropathy, diabetic retinopathy, diabetic thromboticcomplications, interplanting rejection, systemic inflammatory responsesyndrome (SIRS), dialysis- or operation-induced thrombocytopenia,thrombus formation after artificial blood vessel operation or afterartificial valve replacement, restenosis and reocculusion after coronaryintervention such as percutaneous transluminal coronary angioplasty(PTCA) or percutaneous transluminal coronary recanalization (PTCR)surgery, thrombus formation at the time of extracorporeal circulationand the like, agents for the prevention of blood coagulation at the timeof insertion of blood vessel catheter, and agents for the prevention ortreatment of influenza virus infection based on the activity to inhibitgrowth of influenza virus.

When the 5-amidino-2-hydroxybenzenesulfonamide derivatives representedby the above general formula (I) of the present invention andpharmaceutically acceptable salts thereof are employed in the practicaltreatment, they are administered orally or parenterally in the form ofappropriate pharmaceutical compositions such as tablets, powders, finegranules, granules, capsules, injections, solutions, adhesivepreparations, ointments, inhalants, suppositories and the like. Thesepharmaceutical compositions can be formulated in accordance withpharmaceutically conventional methods using conventional pharmaceuticalcarriers, excipients and other additives.

The dosage is appropriately decided depending on the sex, age, bodyweight, degree of symptoms and the like of each patient to be treated,which is approximately within the range of from 1 to 5, 000mg per dayper adult human in case of oral administration and approximately withinthe range of from 0.01 to 500 mg per day per adult human in case ofparenteral administration such as injection, and the daily dose can bedivided into one to several doses per day.

EXAMPLES

The present invention is further illustrated in more detail by way ofthe following Reference Examples, Examples and Test Examples. However,the present invention is not limited thereto.

Reference Example 1 7-Hydroxycroman-2-one

A mixture of 100 g of 7-hydroxycromen-2-one, 10 g of 10% palladium oncarbon, 500 mL of tetrahydrofuran and 800 mL of ethanol was stirredunder a hydrogen atmosphere at 65° C. for 15 hours. To the reactionmixture were added a suspension of 10 g of 10% palladium on carbon in200 mL of ethanol under ice-cooling, and the mixture was stirred under ahydrogen atmosphere at 65° C. for 15 hours. The reaction mixture wasfiltered through a diatomaceous earth, and the filtrate was concentratedunder reduced pressure to give 106.5 g of colorless7-hydroxy-croman-2-one.

¹H-NMR (CDCl₃) δ ppm: 2.75–2.96 (4H, m), 5.81 (1H, br s), 6.59–6.66 (2H,m), 7.04 (1H, d, J=7.9 Hz)

Reference Example 2 7-Benzyloxycroman-2-one

To a stirred suspension of 202.4 g of 7-hydroxy-croman-2-one and 341.0 gof potassium carbonate in N,N-dimethylformamide was added 153.2 mL ofbenzyl chloride at room temperature, and the mixture was stirred at roomtemperature for 15 hours. After the reaction mixture was concentratedunder reduced pressure to remove the solvent, the residue was added to amixture of ethyl acetate and water. The organic layer was separated,washed with water, dried over anhydrous magnesium sulfate, and filtered.The filtrate was concentrated under reduced pressure, and the residuewas triturated in diisopropyl ether-hexane. The solid was collected byfiltration to give 266.1 g of 7-benzyloxycromae-2-one as a pale brownsolid.

¹H-NMR (CDCl₃) δ ppm: 2.73–2.81 (2H, m), 2.90–2.98 (2H, m), 5.05 (2H,s), 6.68 (1H, d, J=2.5 Hz), 6.73 (1H, dd, J=8.3, 2.5 Hz), 7.08 (1H, d,J=8.3 Hz), 7.30–7.46 (5H, m)

Reference Example 3 3-(4-Benzyloxy-2-hydroxyphenyl)propionamide

To a solution of 33.26 g of 7-benzyloxycroman-2-one in 264 mL oftetrahydrofuran was added 82 mL of 28% aqueous ammonia solution at roomtemperature. After the mixture was stirred at room temperature for 20minutes, to the reaction mixture was added 654 mL of 1 mol/Lhydrochloric acid in an ice-bath. The resulted suspension was dilutedwith about 1 L of water, and the precipitate was collected by filtrationto give 34.8 g of 3-(4-benzyloxy-2-hydroxyphenyl)propionamide as acolorless powder.

¹H-NMR (CDCl₃) δ ppm: 2.60–2.70 (2H, m), 2.80–2.90 (2H, m), 5.01 (2H,s), 5.46 (2H, br s), 6.49 (1H, dd, J=8.5, 2.5 Hz), 6.58 (1H, d, J=2.5Hz), 6.93 (1H, d, J=8.5 Hz), 7.28–7.45 (5H, m), 8.67 (1H, s)

Reference Example 4 3-(4-Benzyloxy-2-methoxymethoxyphenyl)propionamide

To a stirred suspension of 5.64 g of 60% sodium hydride in oil in 628 mLof N,N-dimethylformamide was added 34.8 g of3-(4-benzyloxy-2-hydroxyphenyl)propionamide under ice-cooling, and themixture was stirred at 50° C. for 40 minutes. To the reaction mixturewas added 12.39 g of chloromethyl methyl ether under ice-cooling, andthe mixture was stirred at room temperature for 15 hours. After thereaction mixture was concentrated under reduced pressure to remove thesolvent, the residue was poured into a mixture of 500 mL of ethylacetate, 100 mL of toluene, and 200 mL of water. The organic layer wasseparated, washed with water, dried over anhydrous magnesium sulfate,and filtered. The filtrate was concentrated under reduced pressure togive a colorless solid. The solid was triturated in ethylacetate-diisopropyl ether to collect by filtration of 35.3 g of3-(4-benzyloxy-2-methoxymethoxy-phenyl)propionamide as a colorlesssolid.

¹H-NMR (CDCl₃) δ ppm: 2.50 (2H, t, J=7.6 Hz), 2.91 (2H, t, J=7.6 Hz),3.47 (3H, s), 5.02 (2H, s), 5.18 (2H, s), 5.25–5.45 (2H, m), 6.56 (1H,dd, J=8.5, 2.5 Hz), 6.77 (1H, d, J=2.5 Hz), 7.07 (1H, d, J=8.5 Hz),7.30–7.45 (5H, m)

Reference Example 5 2-(4-Benzyloxy-2-methoxymethoxyphenyl)ethylamine

To a solution of 28.42 g of3-(4-benzyloxy-2-methoxy-methoxyphenyl)propionamide and 40.4 mL of1,8-diazabicyclo-[5.4.0]-7-undecene in 895 mL of methanol was added16.04 g of N-bromosuccinimide at 65° C. After the mixture was stirred at65° C. for 15 minutes, to the reaction mixture was added additional16.04 g of N-bromosuccinimide at 65° C. After being stirred at 65° C.for 15 minutes, the resulted mixture was concentrated under reducedpressure to remove the solvent. To the residue were added water andethyl acetate, and the organic layer was separated. The organic layerwas washed with water, dried over anhydrous magnesium sulfate, andfiltered. The filtrate was concentrated under reduced pressure to giveoily product. To a solution of this residue in 242 mL of ethanol wasadded 67.6 mL of 8 mol/L aqueous potassium hydroxide solution, and themixture was refluxed for 15 hours. The reaction mixture was concentratedunder reduced pressure to remove the solvent. To the residue were added500 mL of ethyl acetate, 50 mL of toluene, and 300 mL of water, and theorganic layer was separated. The organic layer was washed with water,dried over anhydrous magnesium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure, and the residue was purified bymedium pressure liquid column chromatography on silica gel (eluent:hexane-ethyl acetate) to give 80.0 g of2-(4-benzyloxy-2-methoxymethoxy-phenyl)ethylamine as a colorless oil.

¹H-NMR (CDCl₃) δ ppm: 1.31 (2H, br s), 2.71 (2H, t, J=6.9 Hz), 2.90 (2H,t, J=6.9 Hz), 3.47 (3H, s), 5.03 (2H, s), 5.17 (2H, s), 6.56 (1H, dd,J=8.2, 2.5 Hz), 6.79 (1H, d, J=2.5 Hz), 7.04 (1H, d, J=8.2 Hz),7.29–7.45 (5H, m)

Reference Example 6 4-(2-Aminoethyl)-3-methoxymethoxyphenol

A mixture of 18.00 g of2-(4-benzyloxy-2-methoxy-methoxyphenyl)ethylamine, 3.6 g of 10%palladium on carbon (Degussa Inc. :E101 NE/W) and 230 mL of ethanol wasstirred under a hydrogen atmosphere at room temperature for 1 hour.After the catalyst was filtered off through a diatomaceous earth, thefiltrate was concentrated under reduced pressure to give 12.65 g of4-(2-aminoethyl)-3-methoxymethoxyphenol as a colorless solid.

¹H-NMR (CD₃OD) δ ppm: 2.65–2.75 (2H, m), 2.75–2.85 (2H, m), 3.45 (3H,s), 5.16 (2H, s), 6.36 (1H, dd, J=8.1, 2.3 Hz), 6.58 (1H, d, J=2.3 Hz),6.94 (1H, d, J=8.1 Hz)

Reference Example 7 N-Cyanomethyl-2,2,2-trifluoroacetamide

Aminoacetonitrile hydrogen sulfate (50 g) and 77 mL of pyridine weresuspended in 300 mL of dichloromethane, and 80 mL of trifluoroaceticanhydride was added to the stirred mixture under ice-cooling. After themixture was stirred at room temperature for 29 hours, the insolublematerial was removed by filtration, and washed with ethyl acetate. Afterthe filtrate was concentrated under reduced pressure, to the residue wasadded water. The mixture was extracted with ethyl acetate, and theorganic layer was washed with diluted hydrochloric acid and water. Afterthe extract was dried over anhydrous magnesium sulfate, the solvent wasremoved under reduced pressure to give 66 g ofN-cyanomethyl-.2,2,2-trifluoroacetamide.

¹H-NMR (CDCl₃) δ ppm: 4.31 (2H, d, J=6.6 Hz), 7.10 (1H, br s)

Reference Example 82,2,2-Trifluoro-N-[2-(2-hydroxy-4-isopropylphenyl)-2-oxoethyl]acetamide

To 250 mL of 1.0 mol/L boron trichloride dichloromethane solution wereadded a solution of 28.5 mL of 3-isopropylphenol in 130 mL ofdichloromethane, 38 g of N-cyanomethyl-2,2,2-trifluoroacetamide and 14.2g of aluminum chloride under an argon atmosphere in an ice-bath withstirring. After the mixture was stirred at room temperature for 16hours, ice and 2 mol/L hydrochloric acid were added to the reactionmixture under ice-cooling. After the mixture was stirred at roomtemperature for 40 minutes, the organic layer was separated, and theaqueous layer was extracted with dichloromethane. The organic layerswere combined, washed with brine, and dried over anhydrous magnesiumsulfate. The solvent was removed under reduced pressure, and 100 mL ofhexane was added to the residue. The generated crystal was collected byfiltration, washed with hexane and dried under reduced pressure to give22.9 g of2,2,2-trifluoro-N-[2-(2-hydroxy-4-isopropylphenyl)-2-oxoethyl]-acetamide.

¹H-NMR (CDCl₃) δ ppm: 1.26 (6H, d, J=8.8 Hz), 2.86–2.98 (1H, m), 4.83(2H, d, J=4.1 Hz), 6.85 (1H, dd, J=8.2, 1.6 Hz), 6.90 (1H, d, J=1.6 Hz),7.42 (1H, br s), 7.59 (1H, d, J=8.2 Hz), 11.42 (1H, br s)

Reference Example 9Ethyl[5-isopropyl-2-[2-(2,2,2-trifluoroacetylamino)ethyl]-phenoxy]acetate

To a solution of 500 mg of2,2,2-trifluoro-N-[2-(2-hydroxy-4-isopropylphenyl)-2-oxoethyl]acetamidein 2.63 mL of trifluoroacetic acid was added 0.94 mL of triethylsilane.After being stirred at room temperature for 13 hours, the reactionmixture was concentrated and dried thoroughly. The obtained residue and382 mg of potassium carbonate were suspended in 10 mL ofN,N-dimethylformamide, and 0.288 mL of ethyl bromoacetate was added tothe stirred mixture under ice-cooling. The mixture was stirred at roomtemperature for 15 hours, and to the reaction mixture was added water.After the mixture was extracted with ethyl acetate, the organic layerwas washed successively with water and brine, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure, andthe obtained residue was purified by column chromatography on silica gel(eluent: ethyl acetate-hexane) to give 535 mg of ethyl[5-isopropyl-2-[2-(2,2,2-trifluoroacetylamino)ethyl]-phenoxy]acetate.

¹H-NMR (DMSO-d₆) δ ppm: 1.10–1.30 (9H, m), 2.75–2.95 (3H, m), 3.35–3.50(2H, m), 4.17 (2H, q, J=7.3 Hz), 4.81 (2H, s), 6.70–6.90 (2H, m), 7.03(1H, d, J=7.5 Hz), 9.40–9.55 (1H, m)

Reference Example 10

The following compound was prepared according to a similar manner tothat described in

Reference Example 9. Ethyl2-[5-isopropyl-2-[2-(2,2,2-trifluoroacetylamino)-ethyl]phenoxy]propionate

¹H-NMR (CDCl₃) δ ppm: 1.18–1.22 (6H, m), 1.25 (3H, t, J=6.9 Hz), 1.64(3H, d, J=6.6 Hz), 2.79–2.93 (2H, m), 2.95–3.02 (1H, m), 3.55–3.64 (1H,m), 3.68–3.76 (1H, m), 4.21 (2H, q, J=6.9 Hz), 4.88 (1H, q, J=6.6 Hz),6.59–6.61 (1H, m), 6.79–6.83(1H, m), 7.05 (1H, d, J=7.3 Hz), 7.16 (1H,br s)

Reference Example 11 Ethyl[2-(2-aminoethyl)-5-isopropylphenoxy]acetatehydrochloride

To a solution of 26.4 g ofethyl[5-isopropyl-2-[2-(2,2,2-trifluoroacetylamino)ethyl]phenoxy]acetatein a mixture of 300 mL of methanol and 15 mL of water was added 30.3 gof potassium carbonate. After the mixture was stirred at roomtemperature for 20 hours, the insoluble material was removed byfiltration, and the filtrate was concentrated under reduced pressure. Tothe residue was added 300 mL of 35% hydrogen chloride ethanol solution,and the mixture was stirred at room temperature for 3 hours. Thereaction mixture was concentrated under reduced pressure to give a crudeproduct of 24.8 g of ethyl [2-(2-aminoethyl)-5-isopropylphenoxy]acetatehydrochloride.

¹H-NMR (DMSO-d₆) δ ppm: 1.17 (6H, d, J=6.9 Hz), 1.21 (3H, t, J=7.3 Hz),2.75–2.95 (3H, m), 2.95–3.05 (2H, m), 4.18 (2H, q, J=7.3 Hz), 4.84 (2H,s), 6.75–6.79 (1H, m), 6.81 (1H, dd, J=7.9, 1.6 Hz), 7.10 (1H, d, J=7.9Hz), 8.13 (3H, br s)

Reference Example 12

The following compound was prepared according to a similar manner tothat described in

Reference Example 11. Ethyl2-[2-(2-aminoethyl)-5-isopropylphenoxy]propionate hydrochloride

¹H-NMR (CDCl₃) δ ppm: 1.12–1.19 (9H, m), 1.54 (3H, d, J=6.5 Hz),2.75–3.11 (5H, m), 4.09–4.18 (2H, m), 5.06 (1H, q, J=6.5 Hz), 6.71 (1H,s), 6.78–6.82 (1H, m), 7.09 (1H, d, J=8.0 Hz), 7.93 (3H, br s)

Reference Example 13 2-Hydroxy-4-isopropylbenzaldehyde

To 100 mL of trifluoroacetic acid were added 25.39 g of3-isopropylphenol and 26.14 g of hexamethylenetetramine. After beingstirred at 60° C. for an hour, the reaction mixture was concentratedunder reduced pressure. To the residue was added diluted hydrochloricacid, and the mixture was stirred at room temperature for 30 minutes.After the reaction mixture was extracted with ethyl acetate, the organiclayer was washed with saturated aqueous sodium bicarbonate solution, andbrine, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: ethyl acetate-hexane) to give 6.69g of 2-hydroxy-4-isopropylbenzaldehyde.

¹H-NMR (CDCl₃) δ ppm: 1.26 (6H, d, J=6.9 Hz), 2.92 (1H, sept, J=6.9 Hz),6.83–6.87 (1H, m), 6.88 (1H, dd, J=7.9, 1.6 Hz), 7.47 (1H, d, J=7.9 Hz),9.83 (1H, s), 11.03 (1H, br s)

Reference Example 14 2-Benzyloxy-4-isopropylbenzaldehyde

2-Hydroxy-4-isopropylbenzaldehyde (6.69 g) and 11.26 g of potassiumcarbonate were suspended with 100 mL of N,N-dimethylformamide, and 5.33mL of benzyl bromide was added to the stirred mixture at roomtemperature. After the mixture was stirred at room temperature for 16hours, the insoluble material was removed by filtration. To the filtratewere added 10 mL of water and 10 mL of diluted hydrochloric acid, andthe mixture was extracted with ethyl acetate. After being washed withbrine, the organic layer was dried over anhydrous magnesium sulfate. Thesolvent was removed under reduced pressure, and the obtained residue waspurified by column chromatography on silica gel (eluent: ethylacetate-hexane) to give 10.44 g of 2-benzyloxy-4-isopropylbenzaldehyde.

¹H-NMR (CDCl₃) δ ppm: 1.25 (6H, d, J=6.9 Hz), 2.88–2.97 (1H, m), 5.19(2H, s), 6.90 (1H, s), 6.92 (1H, d, J=7.9 Hz), 7.32–7.47 (5H, m), 7.79(1H, d, J=7.9 Hz), 10.49 (1H, s)

Reference Example 15 2-Benzyloxy-4-isopropyl-1-(2-nitrovinyl)benzene

To 100 mL of nitromethane were added 10.44 g of2-benzyloxy-4-isopropylbenzaldehyde and 4.71 g of ammonium acetate.After being stirred at external 100° C. for 3 hours, the reactionmixture was concentrated under reduced pressure. The obtained residuewas dissolved in ethyl acetate, and the organic layer was washedsuccessively with 1 mol/L hydrochloric acid, and saturated aqueoussodium bicarbonate solution, and dried over anhydrous magnesium sulfate.The solvent was removed under reduced pressure to give 9.45 g of2-benzyloxy-4-isopropyl-1-(2-nitrovinyl)benzene.

¹H-NMR (CDCl₃) δ ppm: 1.24 (6H, d, J=7.3 Hz), 2.87–2.95 (1H, m), 5.21(2H, s), 6.86–6.93 (2H, m), 7.33–7.48 (6H, m), 7.82 (1H, d, J=13.2 Hz),8.15 (1H, d, J=13.2 Hz)

Reference Example 16 2-(2-Benzyloxy-4-isopropylphenyl)ethylamine

To a stirred suspension of 3.01 g of lithium aluminum hydride in 100 mLof anhydrous diethyl ether was added dropwise a solution of 9.45 g of2-benzyloxy-4-isopropyl-1-(2-nitro-vinyl)benzene in 10 mL of diethylether under ice-cooling with stirring during 10 minutes. After themixture was stirred for 1 hour, 63.5 mL of 2 mol/L sodium hydroxidesolution was added dropwise to the stirred reaction mixture underice-cooling, and the mixture was stirred for 1 hour. To the mixture wasadded anhydrous sodium sulfate, and the mixture was stirred for 15minutes. The insoluble material was filtered off through a diatomaceousearth, and 100 mL of water was added to the filtrate. The mixture wasextracted with ethyl acetate, and the organic layer was washedsuccessively with saturated aqueous sodium bicarbonate solution, andbrine, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure to give 8.56 g of2-(2-benzyloxy-4-isopropylphenyl)-ethylamine.

¹H-NMR (CDCl₃) δ ppm: 1.23 (6H, d, J=6.9 Hz), 2.80 (2H, t, J=6.9 Hz),2.83–2.91 (1H, m), 2.96 (2H, t, J=6.9 Hz), 5.07 (2H, s), 6.76–6.80 (2H,m), 7.08 (1H, d, J=7.3 Hz), 7.29–7.47 (5H, m)

Reference Example 17 tert-ButylN-[2-(2-benzyloxy-4-isopropylphenyl)ethyl]-carbamate

To 100 mL of tetrahydrofuran were added 8.56 g of2-(2-benzyloxy-4-isopropylphenyl)ethylamine and 7.63 g of di-tert-butyldicarbonate, and the mixture was stirred at room temperature for 12hours. The solvent was removed under reduced pressure, and the obtainedresidue was purified by column chromatography on silica gel (eluent:ethyl acetate-hexane) to give 12.00 g of tert-butylN-[2-(2-benzyloxy-4-isopropyl-phenyl)ethyl]carbamate.

¹H-NMR (CDCl₃) δ ppm: 1.23 (6H, d, J=6.9 Hz), 1.41 (9H, s), 2.76–2.91(3H, m), 3.27–3.42 (2H, m), 4.69 (1H, br s), 5.08 (2H, s), 6.75–6.82(2H, m), 7.07 (1H, d, J=7.9 Hz), 7.30–7.48 (5H, m)

Reference Example 18 tert-ButylN-[2-(2-hydroxy-4-isopropylphenyl)ethyl]-carbamate

tert-Butyl N-[2-(2-benzyloxy-4-isopropylphenyl)-ethyl]carbamate (12.00g) was dissolved in 150 mL of ethanol. To the stirred solution was added1.10 g of 10% palladium on carbon under ice-cooling, and the mixture wasstirred under a hydrogen atmosphere and ordinary pressure at 30° C. for16 hours. The insoluble material was filtered, and the filtrate wasconcentrated under reduced pressure to give 6.66 g of tert-butylN-[2-(2-hydroxy-4-isopropylphenyl)ethyl]carbamate.

¹H-NMR (CDCl₃) δ ppm: 1.21 (6H, d, J=6.9 Hz),1.45 (9H, s), 2.75–2.86(3H, m), 3.25–3.32 (2H, m), 4.92 (1H, br s), 6.65–6.71 (1H, m),6.72–6.75 (1H, m), 6.96 (1H, d, J=7.9 Hz), 7.03 (1H, br s)

Reference Example 19 Ethyl4-[2-(2-tert-butoxycarbonylaminoethyl)-5-isopropyl-phenoxy]butyrate

tert-Butyl N-[2-(2-hydroxy-4-isopropylphenyl)ethyl]-carbamate (0.234 g)and 0.116 g of potassium carbonate were suspended in 5 mL ofN,N-dimethylformamide. To the stirred suspension was added dropwise0.126 mL of ethyl 4-bromobutyrate at room temperature, and the mixturewas stirred at room temperature for 16 hours. To the reaction mixturewere added 10 mL of 1 mol/L hydrochloric acid and then 20 mL of water,and the mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and dried over anhydrous magnesium sulfate. Thesolvent was removed under reduced pressure, and the obtained residue waspurified by column chromatography on silica gel (eluent: ethylacetate-hexane) to give 0.283 g of ethyl4-[2-(2-tert-butoxycarbonylaminoethyl)-5-isopropylphenoxy]-butyrate.

¹H-NMR (CDCl₃) δ ppm: 1.24 (6H, d, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz),1.42 (9H, s), 2.10–2.19 (2H, m), 2.53 (2H, t, J=7.3 Hz), 2.72–2.79 (2H,m), 2.81–2.89 (1H, m), 3.28–3.38 (2H, m), 4.02 (2H, t, J=6.0 Hz), 4.15(2H, q, J=7.3 Hz), 4.75 (1H, br s), 6.68–6.71 (1H, m), 6.74–6.79 (1H,m), 7.04 (1H, d, J=7.6 Hz)

Reference Example 20 Ethyl4-[2-(2-aminoethyl)-5-isopropylphenoxy]butyrate hydrochloride

4-[2-(2-tert-Butoxycarbonylaminoethyl)-5-isopropyl-phenoxy]butyrate(0.283 g) was deissolved in 10 mL of 35% hydrogen chloride ethanolsolution, and the mixture was stirred at room temperature for 5 hours.The solvent was removed under reduced pressure to give 0.235 g of ethyl4-[2-(2-aminoethyl)-5-isopropylphenoxy]butyrate hydrochloride.

¹H-NMR (DMSO-d₆) δ ppm: 1.18 (3H, t, J=6.9 Hz), 1.19 (6H, d, J=6.9 Hz),1.94–2.04 (2H, m), 2.78–2.89 (3H, m), 2.90–2.99 (2H, m), 4.01 (2H, t,J=6.3 Hz), 4.08 (2H, q, J=6.9 Hz), 6.75–6.79 (1H, m), 6.81–6.85 (1H, m),7.07 (1H, d, J=7.6 Hz), 7.93 (3H, br s)

Reference Example 21 2-(2-Benzyloxy-4-isopropylphenyl)ethylaminehydrochloride

To a solution of 0.300 g of tert-butylN-[2-(2-benzyloxy-4-isopropylphenyl)ethyl]carbamate in 2 mL of ethanolwas added 2 mL of 21% hydrogen chloride ethanol solution at roomtemperature. After being stirred at the same temperature for 2 hours,the reaction mixture was concentrated under reduced pressure to give0.261 g of 2-(2-benzyloxy-4-isopropylphenyl)ethylamine hydrochloride.

¹H-NMR (CDCl₃) δ ppm: 1.20 (6H, d, J=6.9 Hz), 2.78–2.87 (1H, m),3.04–3.12 (2H, m), 3.15–3.25 (2H, m), 5.10 (2H, s), 6.74 (1H, d, J=7.6Hz), 6.78 (1H, s), 7.14 (1H, d, J=7.6 Hz), 7.33–7.48 (4H, m), 8.25 (3H,br s)

Reference Example 22 5-Carbamoyl-2-methoxybenzenesulfonyl chloride

To 1733 g of chlorosulfonic acid was added in small portions 150 g of4-methoxybenzamide under ice-cooling with stirring during 15 minutes,and the mixture was stirred at room temperature for 14 hours. Afterbeing stirred at 50° C. for additional 1.5 hours, the reaction mixturewas dropped into 7 kg of ice. The precipitate was collected byfiltration, washed with water and hexane to give 230 g of5-carbamoyl-2-methoxybenzenesulfonyl chloride.

¹H-NMR (DMSO-d₆) δ ppm: 3.81 (3H, s), 7.00 (1H, d, J=8.5 Hz), 7.10 (1H,br s), 7.84 (1H, dd, J=8.5, 2.5 Hz), 7.87 (1H, br s), 8.23 (1H, d, J=2.5Hz)

Reference Example 23 5-Cyano-2-methoxybenzenesulfonyl chloride

5-Carbamoyl-2-methoxybenzenesulfonyl chloride (150 g) was suspended in1800 mL of ethyl acetate. After 219 mL of thionyl chloride was droppedto the stirred suspension under ice-cooling, 2.3mL ofN,N-dimethylformamide was added to the mixture. After being stirred at55° C. for 3 hours, the reaction mixture was concentrated under reducedpressure. To the residue were added ethyl acetate and water, and theseparated organic layer was washed with water, saturated aqueous sodiumbicarbonate solution, and brine, and dried over anhydrous magnesiumsulfate. The solvent was removed under reduced pressure, and theobtained crude product was recrystallized from ethyl acetate-hexane togive 86.8 g of 5-cyano-2-methoxybenzenesulfonyl chloride.

¹H-NMR (CDCl₃) δ ppm: 4.16 (3H, s), 7.24 (1H, d, J=8.8 Hz), 7.96 (1H,dd, J=8.8, 2.2 Hz), 8.28 (1H, d, J=2.2 Hz)

Reference Example 24 2-(Methylthio)phenylboronic acid

Magnesium (9.52 g) was suspended in 119 mL of tetrahydrofuran, and tothe suspension were added 3.00 g of 2-bromothioanisole and about 20 mgof iodine. After the reaction was started by heating employing a dryer,72 g of 2-bromothioanisole was dropped to the mixture during 20minutes.After being heated for 1 hour, the reaction mixture was diluted with1000 mL of tetrahydrofuran, and cooled to 0° C. To the mixture was added102 mL of triisopropyl borate at the same temperature, and the mixturewas stirred at room temperature for 4 hours. To the reaction mixture wasadded water, and the solvent was removed under reduced pressure. Theresidue was added 500 mL of 2 mol/L hydrochloric acid, and the mixturewas extracted with 300 mL of diethyl ether. The organic layer wasextracted with 500 mL of 2 mol/L aqueous sodium hydroxide solution, andthe aqueous layer was acidified by addition of concentrated hydrochloricacid under ice-cooling. The residual diethyl ether was removed underreduced pressure, and the precipitate was collected by filtration togive 45.95 g of 2-(methylthio)-phenylboronic acid.

¹H-NMR (DMSO-d₆) δ ppm: 2.50 (3H, s), 6.21–6.29 (2H, br s), 7.34 (1H,td, J=7.3, 1.3 Hz), 7.42 (1H, td, J=7.3, 1.3 Hz), 7.52 (1H, dd, J=7.3,1.3 Hz), 8.01 (1H, dd, J=7.3, 1.3 Hz)

Reference Example 25 Hydroxylammonium acetate

To 100 mL of 50% aqueous hydroxylamine solution was added slowly 86.6 mLof acetic acid under ice-cooling with stirring, and the mixture wasstirred at the same temperature for 40 minutes, then at room temperaturefor 40 minutes. After the reaction mixture was concentrated underreduced pressure, the residue was dissolved in 50 mL of ethanol, and thesolution was concentrated under reduced pressure. To the residue wasadded toluene, and the mixture was concentrated under reduced pressure,and dried to give 76.4 g of hydroxylammonium acetate as a colorlesssolid.

¹H-NMR (DMSO-d₆) δ ppm: 1.88 (3H, s), 7.63 (4H, br s)

Reference Example 265-Cyano-N-[2-(4-hydroxy-2-methoxymethoxyphenyl)ethyl]-2-methoxybenzenesulfonamide

4-(2-Aminoethyl) -3-methoxymethoxyphenol (12.3 g) and 7.9 g of sodiumbicarbonate were suspended in a mixture of 133 mL of tetrahydrofuran and14.4 mL of water, to the suspension was added 18 mL portions of asolution of 14.50 g of 5-cyano-2-methoxybenzensulfonyl chloride in 180mL of tetrahydrofuran every 10 minutes while the internal temperaturewas kept at 10–20° C. After being stirred at room temperature for 8hours, the reaction mixture was purified by column chromatography onaminopropylated silica gel (eluent: ethyl acetate), and recrystallizedfrom ethyl acetate-diisopropyl ether to give 21.87 g of5-cyano-N-[2-(4-hydroxy-2-methoxymethoxyphenyl)-ethyl]-2-methoxybenzenesulfonamideas a colorless crystal.

¹H-NMR (CDCl₃) δ ppm: 2.74 (2H, t, J=6.3 Hz), 3.10–3.20 (2H, m), 3.40(3H, s), 3.81 (3H, s), 4.85–4.95 (2H, m), 5.08 (2H, s), 6.38 (1H, dd,J=8.2, 2.2 Hz), 6.59 (1H, d, J=2.2 Hz), 6.87 (1H, d, J=8.2 Hz), 7.00(1H, d, J=8.5 Hz), 7.78 (1H, dd, J=8.5, 2.2 Hz), 8.16 (1H, d, J=2.2 Hz)

Reference Example 27Ethyl[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]acetate

To a stirred solution of 326 mg of ethyl[2-(2-amino-ethyl)-5-isopropylphenoxy]acetate hydorochloride and 0.452mL of triethylamine in a mixture of 10 mL of tetrahydrofuran and 5 mL ofwater was added 238 mg of 5-cyano-2-methoxybenzene-sulfonyl chlorideunder ice-cooling, and the mixture was stirred at room temperature for 6hours. To the reaction mixture was added 30 mL of water, and the mixturewas extracted with 120 mL of ethyl acetate. The organic layer was washedwith 100 mL of water, and 100 mL of brine, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure, andthe residue was purified by column chromatography on silica gel (eluent:ethyl acetate-hexane) to give 343 mg of ethyl[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate.

¹H-NMR (DMSO-d₆) δ ppm: 1.14 (6H, d, J=6.9 Hz), 1.19 (3H, t, J=7.3 Hz),2.60–2.70 (2H, m), 2.78 (1H, sept, J=6.9 Hz), 3.02–3.07 (2H, m), 3.94(3H, s), 4.15 (2H, q, J=7.3 Hz), 4.70 (2H, s), 6.65 (1H, d, J=1.7 Hz),6.71 (1H, dd, J=7.6, 1.7 Hz), 6.95 (1H, d, J=7.6 Hz), 7.35 (1H, d, J=8.5Hz), 7.49 (1H, br s), 8.00–8.10 (2H, m)

Reference Example 28

The following compounds were prepared according to a similar manner tothat described in Reference Example 26 or 27. Ethyl4-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]butyrate

¹H-NMR (CDCl₃) δ ppm: 1.22 (6H, d, J=6.9 Hz), 1.27 (3H, t, J=7.3 Hz),2.01–2.09 (2H, m), 2.44 (2H, t, J=7.3 Hz), 2.76 (2H, t, J=6.6 Hz),2.80–2.90 (1H, m), 3.11–3.19 (2H, m), 3.79 (3H, s), 3.94 (2H, t, J=6.0Hz), 4.16 (2H, q, J=7.3 Hz), 4.99 (1H, t, J=5.7 Hz), 6.64–6.68 (1H, m),6.71–6.76 (1H, m), 6.94 (1H, d, J=7.6 Hz), 6.99 (1H, d, J=8.8 Hz), 7.78(1H, dd, J=8.8, 2.2 Hz), 8.20 (1H, d, J=2.2 Hz)

N-[2-(2-Benzyloxy-4-isopropylphenyl)ethyl]-5-cyano-2-methoxybenzenesulfonamide

¹H-NMR (CDCl₃) δ ppm: 1.23 (6H, d, J=6.9 Hz), 2.76–2.91 (3H, m),3.14–3.21 (2H, m), 3.66 (3H, s), 4.85–4.91 (1H, m), 4.98 (2H, s),6.74–6.79 (2H, m), 6.92 (1H, d, J=8.5 Hz), 6.97 (1H, d, J=8.2 Hz),7.29–7.43 (5H, m), 7.73 (1H, dd, J=8.5, 1.9 Hz), 8.15 (1H, d, J=1.9 Hz)

Ethyl2-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]propionate

¹H-NMR (CDCl₃) δ ppm: 1.16–1.22 (6H, m), 1.23–1.29 (3H, m), 1.57 (3H, d,J=6.8 Hz), 2.68–2.96 (3H, m), 3.16–3.37 (2H, m), 3.73 (3H, s), 4.15–4.24(2H, m), 4.77 (1H, q, J=6.8 Hz), 5.26 (1H, t, J=5.7 Hz), 6.51–6.53 (1H,m), 6.72–6.76 (1H, m), 6.90 (1H, d, J=7.6 Hz), 6.98 (1H, d, J=8.6 Hz),7.77 (1H, dd, J=8.6, 3.2 Hz), 8.30 (1H, d, J=3.2 Hz)

Reference Example 294-[2-(5-Cyano-2-methoxybenzenesulfonylamino)ethyl]-3-methoxymethoxyphenyltrifluoromethanesulfonate

To a stirred solution of 21.87 g of5-cyano-N-[2-(4-hydroxy-2-methoxymethoxyphenyl)ethyl]-2-methoxybenzene-sulfonamideand 10.21 g of N,N-dimethylaminopyridine in 230 mL of dichloromethanewas added 9.38 mL of trifluoromethanesulfonic anhydride underice-cooling. The mixture was stirred for 1 hour, and about 50 g ofcrushed ice was added to the reaction mixture. The mixture wasconcentrated under reduced pressure to remove dichloromethane, and theresidue was poured into a mixture of 500 mL of ethyl acetate and 200 mLof water. The organic layer was separated, washed with water, dried overanhydrous magnesium sulfate, and filtered. The filtrate was concentratedunder reduced pressure, and the residue was recrystallized from ethylacetate-diisopropyl ether to give 24.75 g of4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-3-methoxymethoxyphenyltrifluoromethanesulfonate as a colorless powder.

¹H-NMR (CDCl₃) δ ppm: 2.86 (2H, t, J=6.6 Hz), 3.15–3.25 (2H, m), 3.44(3H, s), 3.86 (3H, s), 4.89 (1H, t, J=6.0 Hz), 5.16 (2H, s), 6.86 (1H,dd, J=8.5, 2.2 Hz), 7.00–7.05 (2H, m), 7.12 (1H, d, J=8.5 Hz), 7.81 (1H,dd, J=8.5, 2.2 Hz), 8.20 (1H, d, J=2.2 Hz)

Reference Example 305-Cyano-2-methoxy-N-[2-(3-methoxymethoxy-2′-methylthio-biphenyl-4-yl)ethyl]benzenesulfonamide

A mixture of 24.75 g of4-[2-(5-cyano-2-methoxybenzene-sulfonylamino)ethyl]-3-methoxymethoxyphenyltrifluoro-methanesulfonate, 8.32 g of 2-(methylthio)phenylboronic acid,2.73 g of tetrakis(triphenylphosphine)palladium(0), 728 mg oftetra-n-butylammonium bromide, 10.00 g of sodium carbonte, 48 mL ofwater and 285 mL of toluene was heated under an argon atmosphere at 85°C. for 15 hours. The precipitate was collected by filtration, washedsuccessively with ethyl acetate and water to give 19.74 g of5-cyano-2-methoxy-N-[2-(3-methoxy-methoxy-2′-methylthiobiphenyl-4-yl)ethyl]benzenesulfonamideas an yellow powder.

¹H-NMR (CDCl₃) δ ppm: 2.40 (3H, s), 2.88 (2H, t, J=6.3 Hz), 3.19–3.27(2H, m), 3.43 (3H, s), 3.82 (3H, s), 5.04 (1H, t, J=5.7H z), 5.17 (2H,s), 6.95–7.05 (2H, m), 7.08 (1H, d, J=7.6 Hz), 7.10–7.25 (3H, m),7.25–7.30 (1H, m), 7.30–7.40 (1H, m), 7.79 (1H, dd, J=8.8, 2.2 Hz), 8.22(1H, d, J=2.2 Hz)

Reference Example 31

The following compound was prepared according to a similar manner tothat described in

Reference Example 30.N-tert-Butyl-4′-[2-(5-cyano-2-methoxybenzenesulfonylamino)-ethyl]-3′-methoxymethoxybiphenyl-2-sulfonamide

¹H-NMR (CDCl₃) δ ppm: 1.01 (9H, s), 2.89 (2H, t, J=6.6 Hz), 3.23 (2H,m), 3.43 (3H, s), 3.79 (1H, s), 3.96 (3H, s), 4.99 (1H, t, J=6.0 Hz),5.22 (2H, s), 7.06 (1H, dd, J=7.6, 1.6 Hz), 7.09 (1H, d, J=8.8 Hz), 7.15(1H, d, J=7.6 Hz), 7.28–7.35 (2H, m), 7.49 (1H, td, J=7.6, 1.3 Hz), 7.57(1H, td, J=7.6, 1.3 Hz), 7.82 (1H, dd, J=8.8, 2.2 Hz), 8.17 (1H, dd,J=7.6, 1.3 Hz), 8.22 (1H, d, J=2.2 Hz)

Reference Example 325-Cyano-2-methoxy-N-[2-(3′,4′,5′-trifluoro-3-methoxy-methoxybiphenyl-4-yl)ethyl]benzenesulfonamide

A mixture of 10.0 g of4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-3-methoxymethoxyphenyltrifluoromethanesulfonate, 5.33 g of bis(pinacolato)diboron, 467 mg of1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloridedichloromethane complex, 317 mg of1,1′-bis(diphenylphosphino)ferrocenepalladium(II), 5.61 g of potassiumacetate, and 113 mL of 1,4-dioxane was stirred under an argon atmosphereat 80° C. for 15 hours. To the reaction mixture were added 4.02 g of1-bromo-3,4,5-trifluorobenzene, 467mg of1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloridedichloromethane complex, 12.14 g of potassium phosphinate, and 40 mL of1,4-dioxane. The mixture was stirred under argon atmosphere at 80° C.for 24 hours, and ethyl acetate and water were added to the reactionmixture. The organic layer was separated, washed with water, dried overanhydrous magnesium sulfate, and filtered. The filtrate was concentratedunder reduced pressure, and the residue was purified by columnchromatography on aminopropylated silica gel (eluent: ethylacetate-hexane) to give 10.09 g of 5-cyano-2-methoxy-N-[2-(3′,4′,5′-trifluoro-3-methoxymethoxybiphenyl-4-yl)ethyl]benzenesulfonamide.

¹H-NMR (CDCl₃) δ ppm: 2.87 (2H, t, J=6.6 Hz), 3.18–3.26 (2H, m), 3.46(3H, s), 3.85 (3H, s), 4.92 (1H, t, J=6.0 Hz), 5.21 (2H, s), 7.02 (1H,d, J=8.5 Hz), 7.06 (1H, dd,J=7.9, 1.6 Hz), 7.10–7.20 (4H, m), 7.79 (1H,dd, J=8.5, 2.2 Hz), 8.20 (1H, d, J=2.2 Hz)

Reference Example 335-Cyano-N-[2-(2′-methanesulfonyl-3-methoxymethoxybiphenyl-4-yl)ethyl]-2-methoxybenzenesulfonamide

To a stirred suspension of 26.44 g of5-cyano-2-methoxy-N-[2-(3-methoxymethoxy-2′-methylthiobiphenyl-4-yl)ethyl)]-benzenesulfonamideand 35.6 g of sodium bicarbonate in a mixture of 530 mL of acetone and106 mL of water was added two portions of 81.5 g of OXONE (trademark)every 15 minutes under ice-cooling. The mixture was stirred under thesame condition for 3 hours, and 100 mL of di ethyl ether, 100 mL ofwater, and saturated aqueous sodium sulfate solution were added to thestirred reaction mixture under ice-cooling. The obtained mixture wasconcentrated under reduced pressure to remove acetone, and 300 mL ofwater, and diethyl ether-hexane were added to the stirred residue underice-cooling. The mixture was stirred for 30 minutes, and the precipitatewas collected by filtration, washed with water and diethyl ether-hexaneto give 27.1 g of5-cyano-N-[2-(2′-methanesulfonyl-3-methoxymethoxybiphenyl-4-yl)ethyl]-2-methoxybenzenesulfonamideas a white powder.

¹H-NMR (DMSO-d₆) δ ppm: 2.65–2.75 (2H, m), 2.79 (3H, s), 3.05–3.15 (2H,m), 3.30–3.35 (3H, m), 4.00 (3H, s), 5.15 (2H, s), 6.94 (1H, dd, J=7.6,1.6 Hz), 7.06 (1H, d, J=1.6 Hz), 7.16 (1H, d, J=7.6 Hz), 7.35–7.45 (2H,m), 7.66 (1H, td, J=7.6, 1.3 Hz), 7.70–7.80 (2H, m), 8.05–8.15 (3H, m)

Reference Example 345-Cyano-N-[2-(3-hydroxy-2′-methanesulfonylbiphenyl-4-yl)-ethyl]-2-methoxybenzenesulfonamide

To a suspension of 14.89 g of5-cyano-N-[2-(2′-methanesulfonyl-3-methoxymethoxybiphenyl-4-yl)ethyl]-2-methoxybenzenesulfonamidein a mixture of 30 mL of isopropanol and 90 mL of tetrahydrofuran wasadded 11.7 mL of concentrated hydrochloric acid. After being stirred at50° C. for 2 hours, the reaction mixture was diluted with 50 mL ofwater, and extracted with 150 mL of ethyl acetate. The organic layer waswashed with saturated aqueous sodium bicarbonate solution, and brine,dried over anhydrous magnesium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure, and the residue was purified bycolumn chromatography on aminopropylated silica gel (eluent: ethylacetate-methanol) to give 10.22 g of5-cyano-N-[2-(3-hydroxy-2′-methanesulfonylbiphenyl-4-yl)ethyl]-2-Methoxybenzenesulfonamide,colorless and amorphous.

¹H-NMR (CDCl₃) δ ppm: 2.69 (3H, s), 2.87 (2H, t, J=6.9 Hz), 3.20–3.30(2H, m), 3.98 (3H, s), 5.34 (1H, t, J=5.7 Hz), 5.93 (1H, s), 6.88 (1H,dd, J=7.6, 1.6 Hz), 6.97 (1H, d, J=1.6 Hz), 7.05–7.15 (2H, m), 7.33 (1H,dd, J=7.6, 1.3 Hz), 7.56 (1H, td, J=7.6, 1.3 Hz), 7.65 (1H, td, J=7.6,1.3 Hz), 7.82 (1H, dd, J=8.5, 2.2 Hz), 8.15–8.25 (2H, m)

Reference Example 35

The following compounds were prepared according to a similar manner tothat described in

Reference Example 34.5-Cyano-2-methoxy-N-[2-(3′,4′,5′-trifluoro-3-hydroxy-biphenyl-4-yl)ethyl]benzenesulfonamide

¹H-NMR (DMSO-d₆) δ ppm: 2.64 (2H, t, J=7.3 Hz), 3.07 (2H, t, J=7.3 Hz),3.96 (3H, s), 6.93 (1H, d, J=1.9 Hz), 6.99 (1H, dd, J=7.6, 1.9 Hz), 7.05(1H, d, J=7.6 Hz), 7.35 (1H, d, J=8.5 Hz), 7.40–7.50 (2H, m), 7.95–8.05(2H, m)

N-tert-Butyl4′-[2-(5-cyano-2-methoxybenzenesulfonylamino)-ethyl]-3′-hydroxybiphenyl-2-sulfonamide

¹H-NMR (CDCl₃) δ ppm: 1.00 (9H, s), 2.87 (2H, t, J=6.6 Hz), 3.23 (2H,m), 3.98 (3H, s), 5.28 (1H, t, J=5.7 Hz), 6.10 (1H, s), 6.91 (1H, dd,J=7.6, 1.6 Hz), 7.06 (1H, d, J=1.6 Hz), 7.10 (1H, d, J=8.5 Hz),7.13–7.20 (2H, m), 7.29 (1H, dd, J=7.6, 1.3 Hz), 7.48 (1H, td, J=7.6,1.3 Hz), 7.56 (1H, td, J=7.6, 1.3 Hz), 7.82 (1H, dd, J=7.6, 1.3 Hz),8.14 (1H, dd, J=8.5, 2.2 Hz), 8.21 (1H, d, J=2.2 Hz)

Reference Example 36

The following compound was prepared according to the similar manner tothat described in Reference Example 32 and 34.

Methyl4′-[2-(5-cyano-2-methoxybenzenesulfonylamino)-ethyl]-3′-hydroxybiphenyl-2-carboxylate

¹H-NMR (CDCl₃) δ ppm: 2.84 (2H, t, J=6.3 Hz), 3.20–3.30 (2H, m), 3.70(3H, s), 3.90 (3H, s), 5.53 (1H, t, J=5.4 Hz),5.93 (1H, br), 6.67 (1H,d, J=1.6 Hz), 6.78 (1H, dd, J=7.9, 1.6 Hz), 7.00–7.05 (2H, m), 7.41 (1H,td, J=7.6, 1.3 Hz), 7.51 (1H, td, J=7.6, 1.3 Hz), 7.73 (1H, dd, J=8.8,2.2 Hz), 7.77 (1H, dd, J=7.6, 1.3 Hz), 8.21 (1H, d, J=2.2 Hz)

Reference Example 37Ethyl[4-[2-(5-cyano-2-methoxybenzenesulfonylamino)-ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate

To a solution of 5.72 g of5-cyano-N-[2-(3-hydroxy-2′-methanesulfonylbiphenyl-4-yl)ethyl]-2-methoxybenzenesulfonamidein 57 mL of N,N-dimethylformamide were added 2.46 mL ofN,N-diisopropylethylamine and 1.37 mL of ethyl bromoacetate. After beingstirred at 50° C. for 15 hours, and the reaction mixture was poured into100 mL of water, and extracted with a mixture of 150 mL of ethyl acetateand 20 mL of toluene. The organic layer was washed with water and brine,dried over anhydrous magnesium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure, and the residue was purified bycolumn chromatography on aminopropylated silica gel (eluent: ethylacetate-hexane) to give 2.96 g of ethyl[4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate,amorphous.

¹H-NMR (CDCl₃) δ ppm: 1.28 (3H, t, J=6.9 Hz), 2.59 (3H, s), 2.95 (2H, t,J=6.6 Hz), 3.30–3.60 (2H, m), 3.99 (3H, s), 4.23 (2H, q, J=6.9 Hz), 4.68(2H, s), 5.43 (1H, t, J=6.3 Hz), 6.95 (1H, dd, J=7.6, 1.6 Hz), 7.04 (1H,d, J=1.6 Hz), 7.09 (1H, d, J=8.5 Hz), 7.20 (1H, d, J=7.6 Hz), 7.36 (1H,dd, J=7.6, 1.3 Hz), 7.57 (1H, td, J=7.6, 1.3 Hz), 7.65 (1H, td, J=7.6,1.3 Hz), 7.80 (1H, dd, J=8.5, 2.2 Hz), 8.20–8.25 (2H, m)

Reference Example 38

The following compounds were prepared according to a similar manner tothat described in Reference Example 37.

Ethyl[4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-3′,4′,5′-trifluorobiphenyl-3-yloxy]acetate

¹H-NMR (CDCl₃) δ ppm: 1.32 (3H, t, J=7.3 Hz), 2.92 (2H, t, J=6.6 Hz),3.30 (2H, q, J=6.6 Hz), 3.88 (3H, s), 4.27 (2H, q, J=7.3 Hz), 4.68 (2H,s), 5.26 (1H, t, J=6.6 Hz), 6.78 (1H, d, J=1.6 Hz), 7.00–7.14 (4H, m),7.16 (1H, d, J=7.6 Hz), 7.78 (1H, dd, J=8.8, 2.2 Hz), 8.20 (1H, d, J=2.2Hz)

Methyl4′-[2-(5-cyano-2-methoxybenzenesulfonylamino)-ethyl]-3′-ethoxycarbonylmethoxybiphenyl-2-carboxylate

¹H-NMR (CDCl₃) δ ppm: 1.29 (3H, t, J=6.9 Hz), 2.91 (2H, t, J=6.3 Hz),3.25–3.35 (2H, m), 3.68 (3H, s), 3.89 (3H, s), 4.25, (2H, q, J=6.3 Hz),4.59 (2H, s), 5.33 (1H, t, J=6.0 Hz), 6.66 (1H, d, J=1.6 Hz), 6.88 (1H,dd, J=7.6, 1.6 Hz), 7.05 (1H, d, J=8.5 Hz), 7.08 (1H, d, J=7.6 Hz), 7.30(1H, dd, J=7.6, 1.3 Hz), 7.42 (1H, td, J=7.6, 1.3 Hz), 7.53 (1H, td,J=7.6, 1.3 Hz), 7.75–7.85 (2H, m), 8.22 (1H, d, J=2.2 Hz)

Ethyl[2′-tert-butylsulfamoyl-4-[2-(5-cyano-2-methoxy-benzenesulfonylamino)ethyl]biphenyl-3-yloxy]acetate

¹H-NMR (CDCl₃) δ ppm: 0.94 (9H, s), 1.31 (3H, t, J=7.3 Hz), 2.94 (2H, t,J=6.6 Hz), 3.32 (2H, m), 3.86 (1H, s), 3.99 (3H, s), 4.27 (2H, q, J=7.3Hz), 4.72 (2H, s), 5.28 (1H, t, J=6.3 Hz), 6.94 (1H, dd, J=7.6, 1.9 Hz),7.08 (1H, d, J=8.8 Hz), 7.22 (1H, d, J=1.3 Hz), 7.24 (1H, d, J=7.6 Hz),7.33 (1H, dd, J=7.6, 1.3 Hz), 7.48 (1H, td, J=7.6, 1.3 Hz), 7.56 (1H,td, J=7.6, 1.3 Hz), 7.81 (1H, dd, J=8.8, 2.2 Hz), 8.17 (1H, dd, J=7.6,1.3 Hz), 8.21 (1H, d, J=2.2 Hz)

Reference Example 39[2-[2-(5-Cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]aceticacid

To a solution of 4.52 g ofethyl[2-[2-(5-cyano-2-methoxy-benzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetatein ethanol was added 12.3 mL of 2 mol/L sodium hydroxide solution toneutralize. After being stirred at room temperature for 3 hours, thereaction mixture was concentrated, and 1 mol/L hydrochloric acid wasadded to the residue. After the mixture was extracted with ethylacetate, the organic layer was washed with water and brine, and driedover anhydrous magnesium sulfate. The solvent was removed under reducedpressure to give 4.16 g of[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]aceticacid.

¹H-NMR (CDCl₃) δ ppm: 1.22 (6H, d, J=6.3 Hz), 2.80–2.89 (3H, m),3.18–3.24 (2H, m), 3.74 (3H, s), 4.68 (2H, s), 5.35 (1H, t, J=5.7 Hz),6.58–6.62 (1H, m), 6.80 (1H, d, J=7.3 Hz), 6.97 (1H, d, J=7.3 Hz), 6.99(1H, d, J=8.5 Hz), 7.30–8.10 (2H, m), 8.18 (1H, d, J=2.2 Hz)

Reference Example 40

The following compound was prepared according to a similar manner tothat described in

Reference Example 39.4-[2-(5-Cyano-2-methoxybenzenesulfonylamino)ethyl]-3′,4′,5′-trifluorobiphenyl-3-yloxy]aceticacid

¹H-NMR (DMSO-d₆) δ ppm: 2.71 (2H, t, J=7.3 Hz), 3.05–3.20 (2H, m), 3.93(3H, s), 4.78 (2H, s), 7.10–7.15 (2H, m), 7.19 (1H, dd, J=7.9, 1.6 Hz),7.30–7.35 (1H, m), 7.60–7.75 (3H, m), 8.00–8.05 (2H, m), 12.5–13.5 (1H,br)

Reference Example 41Ethyl[2-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]acetylamino]acetate

To a stirred solution of 0.3 g of[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]aceticacid, 0.107 g of glycine ethyl ester hydrochloride and 0.103 g of1-hydroxybenzotriazole monohydrate in N,N-dimethylformamide were added0.106 mL of triethylamine and 0.146 g of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride underice-cooling, and the mixture was stirred at room temperature for 15hours. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with 1 mol/Lhydrochloric acid, saturated aqueous sodium bicarbonate solution, waterand brine, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure, and the obtained residue was purified bycolumn chromatography on silica gel (eluent: ethyl acetate-hexane) togive 0.33 g of ethyl[2-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]-acetylamino]acetate

¹H-NMR (CDCl₃) δ ppm: 1.22 (6H, d, J=7.3 Hz), 1.31 (3H, t, J=7.3 Hz),2.80–3.00 (3H, m), 3.17–3.24 (2H, m), 3.91 (3H, s), 4.16 (2H, d, J=5.5Hz), 4.27 (2H, q, J=7.3 Hz), 4.53 (2H, s), 5.24 (1H, t, J=6.3 Hz), 6.68(1H, d, J=1.1 Hz), 6.83 (1H, dd, J=7.9, 1.1 Hz), 7.01 (1H, d, J=7.9 Hz),7.05 (1H, d, J=8.4 Hz), 7.80 (1H, dd, J=8.4, 2.2 Hz), 8.21 (1H, d, J=2.2Hz)

Reference Example 42

The following compound was prepared according to a similar manner tothat described in Reference Example 41.

Ethyl3-[2-[4-[2-(5-cyano-2-methoxybenzenesulfonylamino)-ethyl]-3′,4′,5′-trifluorobiphenyl-3-yloxy]acetylamino]-propionate

¹H-NMR (DMSO-d₆) δ ppm: 1.14 (3H, t, J=7.3 Hz), 2.78 (2H, t, J=6.9 Hz),3.12 (2H, q, J=6.9 Hz), 3.35–3.45 (2H, m), 3.93 (3H, s), 4.01 (2H, q,J=7.3 Hz), 4.59 (2H, s), 7.10–7.20 (2H, m), 7.22 (1H, dd, J=7.9, 1.6Hz), 7.34 (1H, d, J=8.5 Hz), 7.61–7.66 (1H, m), 7.67–7.75 (2H, m), 7.87(1H, t, J=6.0 Hz), 8.00–8.05 (2H, m)

Reference Example 432-[2-[2-(5-Cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetamide

A mixture of 0.169 g of[2-[2-(5-cyano-2-methoxybenzene-sulfonylamino)ethyl]-5-isopropylphenoxy]aceticacid, 41.8 mg of ammonium chloride, 79.2 mg of 1-hydroxybenzotriazolemonohydrate, 0.272 mL of N,N-diisopropylethylamine and 0.112 g of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride wasstirred at room temperature for 27 hours. The reaction mixture wasdiluted with water, and extracted with ethyl acetate. The organic layerwas washed with saturated aqueous sodium bicarbonate solution and brine,and dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure, and the obtained residue was purified by columnchromatography on aminopropylated silica gel (eluent:dichloromethane-ethyl acetate) to give 151.4 mg of2-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetamide.

¹H-NMR (CDCl₃) δ ppm: 1.22 (6H, d, J=7.3 Hz), 2.83–2.92 (3H, m),3.14–3.21 (2H, m), 3.90 (3H, s), 4.51 (2H, s), 5.21 (1H, br s), 5.87(1H, br s), 6.70 (1H, d, J=1.3 Hz), 6.80 (1H, br s), 6.82 (1H, dd,J=7.9, 1.3 Hz), 7.00 (1H, d, J=7.9 Hz), 7.06 (1H, d, J=8.5 Hz), 7.81(1H, dd, J=8.5, 1.9 Hz), 8.17 (1H, d, J=1.9 Hz)

Reference Example 44

The following compounds were prepared according to a similar manner tothat described in Reference Example 43.

2-[2-[2-(5-Cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]-N,N-dimethylacetamide

¹H-NMR (CDCl₃) δ ppm: 1.22 (6H, d, J=6.9 Hz), 2.80–2.90 (3H, m), 2.99(3H, s), 3.06 (3H, s), 3.21–3.28 (2H, m), 3.80 (3H, s), 4.67 (2H, s),5.71 (1H, t, J=6.0 Hz), 6.64 (1H, d, J=1.3 Hz), 6.77 (1H, dd, J=7.6, 1.3Hz), 6.95 (1H, d, J=7.6 Hz), 6.99 (1H, d, J=8.5 Hz), 7.76 (1H, dd,J=8.5, 2.2 Hz), 8.18 (1H, d, J=2.2 Hz)

5-Cyano-N-[2-[4-isopropyl-2-(2-morpholin-4-yl-2-oxoethoxy)-phenyl]ethyl]-2-methoxybenzenesulfonamide

¹H-NMR (CDCl₃) δ ppm: 1.22 (6H, d, J=6.9 Hz), 2.79–2.90 (3H, m), 3.22(2H, q, J=6.0 Hz), 3.50–3.56 (2H, m), 3.60–3.72 (6H, m), 3.82 (3H, s),4.68 (2H, s), 5.47 (1H, t, J=6.0 Hz), 6.66 (1H, d, J=1.3 Hz), 6.79 (1H,dd, J=7.9, 1.3 Hz), 6.96 (1H, d, J=7.9 Hz), 7.00 (1H, d, J=8.5 Hz), 7.77(1H, dd, J=8.5, 2.2 Hz), 8.18 (1H, d, J=2.2 Hz)

Reference Example 45 (4-Isopropylphenyl)acetonitrile

To a stirred solution of 100 g of 4-isopropylbenzyl chloride in 1500 mLof N,N-dimethylformamide was added 32.0 g of sodium cyanide underice-cooling. The mixture was stirred at 70° C. for 4 hours, and waterwas added to the reaction mixture. The mixture was extracted with ethylacetate, and the organic layer was washed with water and brine, anddried over anhydrous magnesium sulfate. The solvent was removed underreduced pressure to give 96.5 g of (4-isopropylphenyl)acetonitrile.

¹H-NMR (CDCl₃) δ ppm: 1.24 (6H, d, J=6.9 Hz), 2.91 (1H, sept, J=6.9 Hz),3.70 (2H, s), 7.22–7.27 (4H, m)

Reference Example 46 2-(4-Isopropylphenyl)ethylamine hydrochloride

To 1000 mL of 1.0 mol/L boran-tetrahydrofuran complex was added dropwisea solution of 79.6 g of (4-isopropylphenyl)-acetonitrile in 400 mL oftetrahydrofuran under ice-cooling with stirring, and the mixture wasstrred at room temperature for 2 hours. To the stirred reaction mixturewas added 500 mL of methanol under ice-cooling during 30 minutes, andthe mixture was stirred at the same temperature for 20 minutes. Afterthe reaction mixture was concentrated under reduced pressure, to theresidue were added isopropanol and 500 mL of 2 mol/L hydrochloric acid.The solvent was removed under reduced pressure, and the residue wasrecrystallized from isopropanol-diisopropyl ether to give 41.5 g of2-(4-Isopropylphenyl)ethylamine hydrochloride.

¹H-NMR (DMSO-d₆) δ ppm: 1.18 (6H, d, J=6.9 Hz), 2.81–2.92 (3H, m),2.96–3.05 (2H, m), 7.14–7.26 (4H, m), 8.05 (3H, br s)

Reference Example 472,2,2-Trifluoro-N-[2-(4-isopropylphenyl)ethyl]acetamide

To a stirred solution of 2.59 g of 2-(4-isopropyl-phenyl)ethylamine in10 mL of N,N-dimethylformamide were added 4.0 mL of triethylamine and1.95 mL of trifluoroacetic anhydride under ice-cooling, and the mixturewas stirred at room temperature for an hour. To the reaction mixturewere added water and 10 mL of 1 mol/L hydrochloric acid, and the mixturewas extracted three times with 20 mL of ethyl acetate. The organiclayers were combined and washed with water, saturated aqueous sodiumbicarbonate solution, and brine. The mixture was dried over anhydrousmagnesium sulfate, and the solvent was removed under reduced pressure.Hexane was added to the residue, and the crystal was collected byfiltration to give 2.39 g of2,2,2-trifluoro-N-[2-(4-isopropylphenyl)ethyl)acetamide.

¹H-NMR (CDCl₃) δ ppm: 1.24 (6H, d, J=6.9 Hz), 2.79–2.96 (3H, m), 3.60(2H, q, J=6.6 Hz), 6.33 (1H, br s), 7.11 (2H, d, J=7.9 Hz), 7.20 (2H, d,J=7.9 Hz)

Reference Example 485-Isopropyl-2-[2-(2,2,2-trifluoroacetylamino)ethyl]-benzenesulfonylchloride

Chlorosulfonic acid (2.05 mL) was added to 1.6 g of2,2,2-trifluoro-N-[2-(4-isopropylphenyl)ethyl]acetamide, and the mixturewas stirred at room temperature for 3 hours. The reaction mixture waspoured into ice-water, and water was added to the mixture. The mixturewas extracted with ethyl acetate, and the organic layer was washed withbrine, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: ethyl acetate-hexane) to give0.463 g of5-isopropyl-2-[2-(2,2,2-trifluoroacetyl-amino)ethyl]benzenesulfonylchloride.

¹H-NMR (CDCl₃) δ ppm: 1.30 (6H, d, J=6.9 Hz), 3.02 (1H, sept, J=6.9 Hz),3.39 (2H, t, J=7.3 Hz), 3.68–3.77 (2H, m), 6.66 (1H, brs), 7.42 (1H, d,J=7.9 Hz), 7.57 (1H, dd, J=7.9, 1.9 Hz), 7.95 (1H, d, J=1.9 Hz)

Reference Example 49N-[2-(2-tert-Butylsufamoyl-5-isopropylphenyl)ethyl]-2,2,2-trifluoroacetamide

To a solution of 0.463 g of5-isopropyl-2-[2-(2,2,2-trifluoroacetylamino)ethyl]benzenesulfonylchloride in 30 mL of tetrahydrofuran was added 0.500 mL oftert-butylamine. The mixture was sealed and stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressure,and the residue was dissolved in 30 mL of water and 10 mL of 1 mol/Lhydrochloric acid. The mixture was extracted with ethyl acetate, and theorganic layer was washed with water, saturated aqueous sodiumbicarbonate solution, and brine. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was removed under reducedpressure to give 0.481 g ofN-[2-(2-tert-butylsufamoyl-5-isopropylphenyl)ethyl]-2,2,2-trifluoroacetamide.

¹H-NMR (CDCl₃) δ ppm: 1.21–1.35 (15H, m), 2.90–3.05 (1H, m), 3.22–3.36(2H, m), 3.61–3.75 (2H, m), 4.54–4.66 (1H, m), 7.32–7.49 (2H, m),7.84–7.95 (1H, m)

Reference Example 502-(2-Aminoethyl)-N-tert-butyl-5-isopropylbenzenesulfonamide

To a solution of 0.481 g ofN-[2-(2-tert-butylsufamoyl-5-isopropylphenyl)ethyl]-2,2,2-trifluoroacetamidein 5 mL of ethanol was added 5 mL of 2 mol/L sodium hydroxide solution,and the mixture was allowed to stand at room temperature for 4 hours. Tothe reaction mixture was added 5 mL of 2 mol/L hydrochloric acid, andthe mixture was concentrated under reduced pressure. To the residue wasadded saturated aqueous sodium bicarbonate solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure to give 0.288 g of2-(2-aminoethyl)-N-tert-butyl-5-isopropylbenzenesulfonamide.

¹H-NMR (CDCl₃) δ ppm: 1.20–1.28 (15H, m), 2.94 (1H, sept, J=6.9 Hz),3.09 (2H, t, J=6.6 Hz), 3.21 (2H, t, J=6.6 Hz), 7.23–7.28 (1H, m), 7.33(1H, dd, J=7.9, 1.9 Hz), 7.91 (1H, d, J=1.9 Hz)

Reference Example 513-[[2-(2-tert-Butylsulfamoyl-4-isopropylphenyl)ethyl]-sulfamoyl]-4-methoxybenzamide

To a suspension of 241 mg of 5-carbamoyl-2-methoxybenzenesulfonylchloride and 288 mg of2-(2-aminoethyl)-N-tert-butyl-5-isopropylbenzenesulfonamide in 10 mL ofN,N-dimethylformamide was added 0.32 mL of triethylamine, and themixture was stirred at room temperature for 3 days. To the reactionmixture was added 30 mL of water, and the mixture was stirred at thesame temperature for 1 hour. To the mixture was added 10 mL of 1 mol/Lhydrochloric acid, and the mixture was extracted three times with 20 mLof ethyl acetate. The organic layers were combined and washed with 30 mLof water, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure to give 426 mg of3-[[2-(2-tert-butylsulfamoyl-4-isopropylpheyl)ethyl]sulfamoyl]-4-methoxybenzamide.

¹H-NMR (CDCl₃) δ ppm: 1.23 (6H, d, J=6.9 Hz), 1.25 (9H, s), 2.86–2.97(1H, m), 3.13–3.20 (2H, m), 3.21–3.30 (2H, m), 3.99 (3H, s), 5.20 (1H,br s), 5.37 (1H, t, J=6.0 Hz), 5.43–5.69 (1H, br), 6.60–6.88 (1H, br),7.05 (1H, d, J=8.8 Hz), 7.14(1H, d, J=7.9 Hz), 7.25–7.30 (1H, m), 7.88(1H, d, J=1.9 Hz), 8.13 (1H, dd, J=8.8, 2.5 Hz), 8.32 (1H, d, J=2.5 Hz)

Reference Example 52N-tert-Butyl-2-[2-(5-cyano-2-methoxybenzenesulfonylamino)-ethyl]-5-isopropylbenzenesulfonamide

To a stirred solution of 420 mg of3-[[2-(2-tert-butyl-sulfamoyl-4-isopropylphenyl)ethyl]sulfamoyl]-4-methoxy-benzamidein 30 mL of dichloromethane were added 0.48 mL of triethylamine and0.245 mg of trifluoroacetic anhydride under ice-cooling, and the mixturewas stirred at room temperature overnight. To the reaction mixture wasadded 1 mL of triethylamine, and the mixture was stirred at the sametemperature for 2 hours. To the reaction mixture were added water and 30mL of 1 mol/L hydrochloric acid, and the mixture was extracted threetimes with 30 mL of dichloromethane. The organic layers were combined,washed with water, and brine, and dried over anhydrous magnesiumsulfate. After the solvent was removed under reduced pressure, ethylacetate and hexane were added to the residue, and the crystal wascollected by filtration to give 325 mg ofN-tert-butyl-2-[2-(5-cyano-2-methoxy-benzenesulfonylamino)ethyl]-5-isopropylbenzenesulfonamide.

¹H-NMR (CDCl₃) δ ppm: 1.23 (9H, s), 1.25 (6H, d, J=6.9 Hz), 2.93 (1H,sept, J=6.9 Hz), 3.17 (2H, t, J=6.6 Hz), 3.22–3.29 (2H, m), 3.94 (3H,s), 4.36 (1H, br s), 5.43 (1H, t, J=5.7 Hz), 6.99 (1H, d, J=8.5 Hz),7.20 (1H, d, J=7.9 Hz), 7.29 (1H, dd, J=7.9, 1.6 Hz), 7.79 (1H, dd,J=8.5, 1.9 Hz), 7.84 (1H, d, J=1.6 Hz), 8.15 (1H, d, J=1.9 Hz)

Reference Example 53Ethyl[2-[2-[(5-cyano-2-methoxybenzenesulfonyl)-(2-methyl-1,3-thiazole-4-ylmethyl)amino]ethyl]-5-isopropylphenoxy]-acetate

A suspension of 300 mg ofethyl[2-(2-(5-cyano-2-methoxy-benzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate,132 mg of 4-chloromethyl-2-methyl-1,3-thiazole hydrochloride and 189 mgof potassium carbonate in 2.0 mL of N,N-dimethylformamide was stirred atroom temperature for 18 hours, then at 50° C. for 3 hours. To thereaction mixture were added 60 mg of4-chloromethyl-2-methyl-1,3-thiazole hydrochloride and 45 mg ofpotassium carbonate, and the mixture was stirred at the same temperaturefor 2.7 hours. To the reaction mixture were added 60 mg of4-chloromethyl-2-methyl-1,3-thiazole hydrochloride and 45 mg ofpotassium carbonate, and the mixture was stirred at the same temperaturefor 3 hours. Furthermore, to the reaction mixture was added 2 mL ofN,N-dimethylformamide, and the mixture was stirred at the sametemperature for 1.5 hours. To the reaction mixture were added water andsaturated aqueous sodium bicarbonate solution, and the mixture wasextracted with ethyl acetate. The organic layer was washed with water,aqueous sodium chloride solution, and brine, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure, andthe residue was purified by column chromatography on silica gel (eluent:ethyl acetate-hexane) to give 311 mg of ethyl[2-[2-[(5-cyano-2-methoxybenzenesulfonyl)-(2-methyl-1,3-thiazol-4-ylmethyl)amino)ethyl]-5-isopropylphenoxy]acetate.

¹H-NMR (CDCl₃) δ ppm: 1.19 (6H, d, J=6.9 Hz), 1.27 (3H, t, J=7.3 Hz),2.60 (3H, s), 2.76–2.87 (3H, m), 3.57–3.65 (2H, m), 3.92 (3H, s), 4.24(2H, q, J=7.3 Hz), 4.56 (2H, s), 4.67 (2H, s), 6.49 (1H, d, J=1.6 Hz),6.73 (1H, dd, J=7.6, 1.6 Hz), 6.95 (1H, d, J=8.5 Hz), 6.97 (1H, d, J=7.6Hz), 7.02 (1H, s), 7.71 (1H, dd, J=8.5, 2.2 Hz), 8.22 (1H, d, J=2.2 Hz)

Reference Example 54Amino-[4-benzyloxy-3-[[2-[4-isopropyl-2-(ethoxycarbonylmethoxy)phenyl]ethyl]sulfamoyl]phenyl]methylenecarbamoyloxymethyl2,2-dimethylpropionate

To a solution of 131 mg of ethyl[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]-acetatein 5 mL of N,N-dimethylformamide was added 0.91 mL ofN,N-diisopropylethylamine. To the stirred mixture was added 0.069 mL ofbenzyl bromide at 40° C., and the mixture was stirred at roomtemperature over night. To the reaction mixture were added 0.91 mL ofN,N-diisopropylethylamine and 86 mg of 4-nitrophenoxycarbonyloxymethyl2,2-dimethylpropionate, and the mixture was stirred at room temperaturefor 6 hours. To the reaction mixture were added 10 mL of water and 10 mLof brine, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, and dried over anhydrous magnesium sulfate.The solvent was removed under reduced pressure, and the residue waspurified by column chromatography on silica gel (eluent: ethylacetate-hexane) to give 99 mg ofamino-[4-benzyloxy-3-[[2-[4-isopropyl-2-(ethoxycarbonylmethoxy)phenyl]-ethyl]sulfamoyl]phenyl]methylenecarbamoyloxymethyl2,2-dimethylpropionate.

¹H-NMR (CDCl₃) δ ppm: 1.19 (6H, d, J=6.9 Hz), 1.22 (9H, s), 1.27 (3H, t,J=7.3 Hz), 2.70–2.86 (3H, m), 3.17–3.25 (2H, m), 4.21 (2H, q, J=7.3 Hz),4.47 (2H, s), 5.05–5.11 (1H, m), 5.17 (2H, s), 5.86 (2H, s), 6.50 (1H,d, J=1.6 Hz), 6.71 (1H, dd, J=7.6, 1.6 Hz), 6.86 (1H, d, J=7.6 Hz), 7.04(1H, d, J=8.8 Hz), 7.29–7.48 (6H, m), 8.28 (1H, dd, J=8.8, 2.5 Hz), 8.32(1H, d, J=2.5 Hz), 9.40–9.80 (1H, br)

Reference Example 55

The following compounds were prepared according to a similar manner tothat described in

Reference Example 54.Amino-[4-benzyloxy-3-[[2-[4-isopropyl-2-(ethoxycarbonylmethoxy)phenyl]ethyl]sulfamoyl]phenyl]methylenecarbamoyloxymethyl2-acetoxy-2-methylpropionate

¹H-NMR (CDCl₃) δ ppm: 1.19 (6H, d, J=6.9 Hz), 1.27 (3H, t, J=7.3 Hz),1.56 (6H, s), 2.04 (3H, s), 2.73 (2H, t, J=6.9 Hz), 2.81 (1H, sept,J=6.9 Hz), 3.17–3.24 (2H, m), 4.21 (2H, q, J=7.3 Hz), 4.47 (2H, s), 5.09(1H, t, J=6.0 Hz),5.16 (2H, s), 5.88 (2H, s), 6.50 (1H, d, J=1.6 Hz),6.70 (1H, dd, J=7.6, 1.6 Hz), 6.86 (1H, d, J=7.6 Hz), 6.88–7.17 (1H, m),7.30–7.48 (5H, m), 8.27 (1H, dd, J=8.8, 2.5 Hz), 8.32 (1H, d, J=2.5 Hz),9.20–9.90 (1H, br)

Ethyl[4-[2-[5-[amino(butoxycarbonylimino)methyl]-2-benzyloxybenzenesulfonylamino]ethyl]-2′-methanesulfonyl-biphenyl-3-yl]oxyacetate

¹H-NMR (CDCl₃) δ ppm: 0.95 (3H, t, J=7.3 Hz), 1.24 (3H, t, J=7.3 Hz),1.39–1.50 (2H, m), 1.66–1.76 (2H, m), 2.54 (3H, s), 2.85 (2H, t, J=6.9Hz), 3.21–3.30 (2H, m), 4.12–4.21 (4H, m), 4.58 (2H, s), 5.18 (1H, t,J=6.0 Hz), 5.29 (2H, s), 6.89 (1H, dd, J=7.6, 1.6 Hz), 6.98 (1H, d,J=1.6 Hz), 7.098 (1H, d, J=7.6 Hz), 7.103 (1H, d, J=8.8 Hz), 7.32 (1H,dd, J=7.6, 1.3 Hz), 7.34–7.43 (3H, m), 7.44–7.50 (2H, m), 7.55 (1H, td,J=7.6, 1.6 Hz), 7.63 (1H, td, J=7.6, 1.3 Hz), 8.22 (1H, dd, J=7.6, 1.6Hz), 8.26 (1H, dd, J=8.8, 2.5 Hz), 8.33 (1H, d, J=2.5 Hz), 9.20–10.00(1H, br)

Example 1Ethyl[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)-ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate(Compound 1)

To a solution of 4.62 g of ethyl[4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetatein 40 mL of N,N-dimethylformamide was added 1.03 g of lithium chloride,and the mixture was stirred at 140° C for 2 hours. After being cooled toroom temperature, the reaction mixture was poured into a mixture of 60mL of ethyl acetate, 6 mL of toluene, and 32 mL of 1 mol/L hydrochloricacid. The organic layer was separated, and washed with 1 mol/Lhydrochloric acid and brine. The organic layer was dried over anhydrousmagnesium sulfate, and filtered. The filtrate was concentrated underreduced pressure, and the residue was purified by column chromatographyon aminopropylated silica gel (eluent: acetic acid-ethyl acetate) togive 3.67 g of ethyl[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonyl-biphenyl-3-yloxy]acetate,colorless and amorphous.

¹H-NMR (DMSO-d₆) δ ppm: 1.14 (3H, t, J=7.3 Hz), 2.71 (3H, s), 2.75–2.82(2H, m), 3.07–3.16 (2H, m), 4.10 (2H, q, J=7.3 Hz), 4.75 (2H, s),6.90–6.95 (2H, m), 7.12 (1H, d, J=8.5 Hz), 7.20–7.30 (1H, m), 7.38 (1H,dd, J=7.6, 1.3 Hz), 7.45–7.60 (1H, br s), 7.65 (1H, td, J=7.6, 1.3 Hz),7.75 (1H, td, J=7.6, 1.3 Hz), 7.87 (1H, dd, J=8.5, 2.2 Hz), 8.01 (1H, d,J=2.2 Hz), 8.07 (1H, dd, J=7.6, 1.3 Hz), 11.80–12.30 (1H, br)

Example 2Ethyl[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]acetate(Compound 2)

To a solution of 148 mg ofethyl[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetatein 3 mL of N,N-dimethylformamide was added 41 mg of lithium chloride,and the mixture was stirred at 140° C. for 3 hours. After being cooledto room temperature, the reaction mixture was concentrated under reducedpressure. To the residue was added aqueous 10% citric acid solution toadjust pH4, and the mixture was extracted with 100 mL of ethyl acetate.The organic layer was washed with water and brine, and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure to give 139 mg ofethyl[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]acetate.

¹H-NMR (DMSO-d₆) δ ppm: 1.14 (6H, d, J=6.9 Hz), 1.18 (3H, t, J=7.3 Hz),2.60–2.70 (2H, m), 2.78 (1H, sept, J=6.9 Hz), 2.95–3.10 (2H, m), 4.14(2H, q, J=7.3 Hz), 4.73 (2H, s), 6.66 (1H, d, J=1.4 Hz), 6.72 (1H, dd,J=7.9, 1.4 Hz), 6.97 (1H, d, J=7.9 Hz), 7.09 (1H, d, J=8.5 Hz), 7.45(1H, t, J=5.7 Hz), 7.85 (1H, dd, J=8.5, 2.3 Hz), 7.98 (1H, d, J=2.3 Hz),11.95 (1H, br s)

Example 3

The following compounds were prepared according to a similar manner tothat described in Example 1 or 2.

Ethyl[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-3′,4′,5′-trifluorobiphenyl-3-yloxy]acetate(Compound 3)

¹H-NMR (DMSO-d₆) δ ppm: 1.19 (3H, t, J=7.3 Hz), 2.70–2.80 (2H, m),3.05–3.15 (2H, m), 4.15 (2H, q, J=7.3 Hz), 4.90 (2H, s), 7.06 (1H, d,J=8.5 Hz), 7.15–7.25 (3H, m), 7.48 (1H, t, J=5.7 Hz), 7.65–7.75 (2H, m),7.83 (1H, dd, J=8.5, 2.2 Hz), 7.96(1H, d, J=2.2 Hz), 11.93 (1H, s)

Methyl4′-[2-(5-cyano-2-hydroxybenzenesulfonylamino)-ethyl]-3′-ethoxycarbonylmethoxybiphenyl-2-carboxylate(Compound 4)

¹H-NMR (CDCl₃) δ ppm: 1.32 (3H, t, J=7.3 Hz), 2.94 (2H, t, J=6.0 Hz),3.30–3.40 (2H, m), 3.79 (3H, s), 4.31 (2H, q, J=7.3 Hz), 4.50 (2H, s),5.84 (1H, t, J=5.0 Hz), 6.60(1H, d, J=1.6 Hz), 6.82 (1H, dd, J=7.6, 1.6Hz), 6.89 (1H, d, J=8.5 Hz), 7.05 (1H, d, J=7.6 Hz), 7.32 (1H, dd,J=7.9, 1.3 Hz), 7.44 (1H, td, J=7.9, 1.3 Hz), 7.55–7.60 (2H, m), 7.91(1H, dd, J=7.9, 1.3 Hz), 8.06 (1H, d, J=2.2 Hz), 8.90–9.10 (1H, br)

Ethyl[2-[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]acetylamino]acetate(Compound 5)

¹H-NMR (CDCl₃) δ ppm: 1.23 (6H, d, J=6.9 Hz), 1.35 (3H, t, J=6.9 Hz),2.84–2.92 (3H, m), 3.22–3.28 (2H, m), 4.18 (2H, d, J=5.4 Hz), 4.32 (2H,q, J=6.9 Hz), 4.53 (2H, s), 5.89–5.94 (1H, m), 6.65 (1H, d, J=1.3 Hz),6.85 (1H, dd, J=7.9, 1.3 Hz), 7.03–7.10 (3H, m), 7.65 (1H, dd, J=8.8,2.2 Hz), 7.95 (1H, d, J=2.2 Hz), 9.35 (1H, br s)

2-[2-[2-(5-Cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetamide(Compound 6)

¹H-NMR (DMSO-d₆) δ ppm: 1.16 (6H, d, J=6.9 Hz), 2.68–2.74 (2H, m),2.77–2.84 (1H, m), 2.98–3.06 (2H, m), 4.41 (2H, s), 6.70 (1H, d, J=1.3Hz), 6.73 (1H, dd, J=7.6, 1.3 Hz), 6.98 (1H, d, J=7.6 Hz), 7.11 (1H, d,J=8.8 Hz), 7.24 (1H, br s), 7.47–7.54 (2H, m), 7.86 (1H, dd, J=8.8, 2.5Hz), 7.98 (1H, d, J=2.5 Hz), 12.00 (1H, br s)

Ethyl4-[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]acetate(Compound 7)

¹H-NMR (CDCl₃) δ ppm: 1.23 (6H, d, J=6.9 Hz), 1.29 (3H, t, J=7.3 Hz),2.09–2.17 (2H, m), 2.52 (2H, t, J=7.3 Hz), 2.76 (2H, t, J=6.9 Hz),2.81–2.90 (1H, m), 3.14–3.24 (2H, m), 4.00 (2H, t, J=6.0 Hz), 4.19 (2H,q, J=7.3 Hz), 5.53 (1H, t, J=5.7 Hz), 6.66 (1H, d, J=1.3 Hz), 6.74 (1H,dd, J=7.6, 1.3 Hz), 6.94 (1H, d, J=7.6 Hz), 7.05 (1H, d, J=8.8 Hz), 7.63(1H, dd, J=8.8, 1.9 Hz), 7.94 (1H, d, J=1.9 Hz), 9.73 (1H, br s)

N-[2-(2-Benzyloxy-4-isopropylphenyl)ethyl]-5-cyano-2-hydroxybenzenesulfonamide(Compound 8)

¹H-NMR (CDCl₃) δ ppm: 1.24 (6H, d, J=6.9 Hz), 2.78 (2H, t, J=6.3 Hz),2.83–2.93 (1H, m), 3.24 (2H, t, J=6.3 Hz), 5.04 (2H, s), 5.29 (1H, brs), 6.77 (1H, d, J=7.9 Hz), 6.80 (1H, s), 6.94 (1H, d, J=7.9 Hz), 7.00(1H, d, J=8.5 Hz), 7.29–7.49 (5H, m), 7.58 (1H, dd, J=8.5, 1.9 Hz), 7.69(1H, d, J=1.9 Hz)

Ethyl2-[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]propionate(Compound 9)

¹H-NMR (CDCl₃) δ ppm: 1.17–1.23 (6H, m), 1.32 (3H, t, J=7.0 Hz), 1.63(3H, d, J=6.8 Hz), 2.59–2.66 (1H, m), 2.79–2.87 (1H, m), 3.05–3.19 (2H,m), 3.47–3.56 (1H, m), 4.25–4.35 (2H, m), 4.91 (1H, q, J=6.8 Hz),6.31–6.37 (1H, m), 6.50–6.53 (1H, m), 6.71–6.75 (1H, m), 6.91 (1H, d,J=7.6 Hz), 6.99 (1H, d, J=8.7 Hz), 7.59 (1H, dd, J=8.7, 2.2 Hz), 7.93(1H, d, J=2.2 Hz), 9.39 (1H, br s)

2-[2-[2-(5-Cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]-N,N-dimethylacetamide(Compound 10)

¹H-NMR (DMSO-d₆) δ ppm: 1.15 (6H, d, J=6.9 Hz), 2.61–2.70 (2H, m),2.72–2.84 (1H, m), 2.84 (3H, s), 2.99 (3H, s), 3.00–3.10 (2H, m), 4.74(2H, s), 6.66–6.75 (2H, m), 6.95 (1H, d, J=7.9 Hz), 7.12 (1H, d, J=8.3Hz), 7.42–7.51 (1H, m), 7.85 (1H, dd, J=8.3, 2.2 Hz), 7.97 (1H, d, J=2.2Hz), 12.00 (1H, br s)

5-Cyano-2-hydroxy-N-[2-[4-isopropyl-2-(2-morpholin-4-yl-2-oxoethoxy)phenyl]ethyl]benzenesulfonamide(Compound 11)

¹H-NMR (DMSO-d₆) δ ppm: 1.15 (6H, d, J=6.9 Hz), 2.61–2.69 (2H, m),2.74–2.83 (1H, m), 2.99–3.10 (2H, m), 3.42–3.52 (4H, m), 3.53–3.63 (4H,m), 4.76 (2H, s), 6.68–6.75 (2H, m), 6.96 (1H, d, J=7.6 Hz), 7.10 (1H,d, J=8.2 Hz), 7.47 (1H, t, J=5.7 Hz), 7.85 (1H, dd, J=8.2, 1.9 Hz), 7.98(1H, d, J=1.9 Hz), 11.95 (1H, br s)

Ethyl[2′-tert-butylsulfamoyl-4-[2-(5-cyano-2-hydroxy-benzenesulfonylamino)ethyl]biphenyl-3-yloxy]acetate(Compound 12)

¹H-NMR (DMSO-d₆) δ ppm: 0.92 (9H, s), 1.16 (3H, t, J=6.9 Hz), 2.70–2.80(2H, m), 3.00–3.15 (2H, m), 4.12 (2H, q, J=6.9 Hz), 4.71 (2H, s), 6.89(1H, dd, J=7.6, 1.6 Hz), 6.95 (1H, d, J=1.6 Hz), 7.00–7.10 (1H, br s),7.10–7.50 (4H, m), 7.54 (1H, td, J=7.6, 1.3 Hz), 7.62 (1H, td, J=7.6,1.3 Hz), 7.78 (1H, br s), 7.94 (1H, br s), 8.03 (1H, dd, J=7.6, 1.3 Hz),11.50–12.50 (1H, br)

Ethyl[2-[2-[(5-cyano-2-hydroxybenzenesulfonyl)-(2-methyl-1,3-thiazole-4-ylmethyl)amino)ethyl]-5-isoprpoylphenoxy]-acetate(Compound 13)

¹H-NMR (DMSO-d₆) δ ppm: 1.08–1.20 (9H, m), 2.56–2.65 (5H, m), 2.68–2.83(1H, m), 3.16–3.36 (2H, m), 4.12 (2H, q, J=7.3 Hz), 4.62 (2H, s), 4.68(2H, s), 6.12 (1H, d, J=8.8 Hz), 6.55–6.65 (2H, m), 6.66–6.72 (1H, m),6.83–6.89 (1H, m), 7.09 (1H, dd, J=8.8, 2.5 Hz), 7.19 (1H, s), 7.58–7.63(1H, m)

N-tert-Butyl-2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)-ethyl]-5-isoprpoylbenzenesulfonamide(Compound 14)

¹H-NMR (CDCl₃) δ ppm: 1.20–1.31 (15H, m), 2.93–3.01 (1H, m), 3.14–3.24(2H, m), 3.30–3.41 (2H, m), 4.41–4.55 (1H, m), 5.55–6.30 (1H, br),6.97–7.09 (1H, m), 7.11–7.21 (1H, m), 7.56–7.66 (1H, m), 7.81–7.90 (1H,m), 7.97–8.11 (1H, m)

Example 4

The following compound was prepared according to the similar manner tothat described in Reference Example 37 and Example 1 or 2.

Ethyl3-[2-[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)-ethyl]-3′,4′,5′-trifluorobiphenyl-3-yloxy]acetylamino]-propionate(Compound 15)

¹H-NMR (DMSO-d₆) δ ppm: 1.14 (3H, t, J=7.3 Hz), 2.80 (2H, t, J=7.3 Hz),3.07–3.14 (2H, m), 3.35–3.45 (2H, m), 4.01 (2H, q, J=7.3 Hz), 4.60 (2H,s), 7.07 (1H, d, J=8.5 Hz),7.15–7.25(3H, m), 7.47–7.54(1H, m), 7.65–7.75(2H, m), 7.83 (1H, dd, J=8.5, 2.2 Hz), 7.87 (1H, t, J=6.0 Hz), 7.96 (1H,d, J=2.2 Hz), 11.96 (1H, br s)

Example 55-Cyano-N-[2-(2-hydrazinocarbonylmethoxy-4-isopropyl-phenyl)ethyl]-2-hydroxybenzenesulfonamide(Compound 16)

Ethyl[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)-ethyl]-5-isoproylphenoxy]acetate(0.266 g) was dissolved in 5 mL of ethanol. To the solution was added0.087 mL of hydrazine monohydrate at room temperature, and the mixturewas refluxed for 1 hour. The solvent was removed under reduced pressureto give 0.258 g of5-cyano-N-[2-(2-hydrazinocarbonylmethoxy-4-isopropylphenyl)ethyl]-2-hydroxybenzenesulfonamide.

¹H-NMR (DMSO-d₆) δ ppm: 1.17 (6H, d, J=6.9 Hz), 2.66–2.73 (2H, m),2.75–2.84 (3H, m), 4.47 (2H, s), 5.42 (1H, br s), 6.30 (1H, d, J=8.8Hz), 6.73–6.77 (2H, m), 7.01 (1H, d, J=7.9 Hz), 7.22 (1H, dd, J=8.8, 2.5Hz), 7.56 (1H, d, J=2.5 Hz), 9.00–9.60 (1H, m)

Example 65-Cyano-2-hydroxy-N-[2-[4-isopropyl-2-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-ylmethoxy)phenyl]ethyl]benzenesulfonamide(Compound 17)

5-Cyano-N-[2-(2-hydrazinocarbonylmethoxy-4-isopropylphenyl)ethyl]-2-hydroxybenzenesulfonamide(0.258 g) was dissolved in 10 mL of tetrahydrofuran. To the stirredsolution was added 0.177 g of triphosgene under ice-cooling, and themixture was stirred at room temperature for 30 minutes. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure to give 0.26 g of5-cyano-2-hydroxy-N-[2-[4-isopropyl-2-(5-oxo-4,5-dihydro[1,3,4]-oxadiazol-2-ylmethoxy)phenyl]ethyl]benzenesulfonamide.

¹H-NMR (CDCl₃) δ ppm: 1.23 (6H, d, J=6.9 Hz), 2.74–2.91 (3H, m),3.18–3.24 (2H, m), 4.96 (2H, s), 5.50–5.55 (1H, m), 6.70–6.71 (1H, m),6.81–6.85 (1H, m), 6.99 (1H, d, J=8.5 Hz), 7.07 (1H, d, J=8.5 Hz), 7.64(1H, dd, J=8.8, 1.9 Hz), 7.92 (1H, d, J=1.9 Hz), 9.17–9.57 (2H, m)

Example 75-Cyano-2-hydroxy-N-[2-(2-hydroxy-4-isopropylphenyl)-ethyl]benzenesulfonamide(Compound 18)

To a stirred solution of 0.203 g ofN-[2-(2-benzyloxy-4-isopropylphenyl)ethyl]-5-cyano-2-hydroxybenzenesulfonamidein ethanol was added 0.04 g of 10% palladium on carbon, and the mixturewas stirred under a hydrogen atmosphere and ordinary pressure for 3hours. After the insoluble material was removed by filtration, thefiltrate was concentrated under reduced pressure to give 0.143 g of5-cyano-2-hydroxy-N-[2-(2-hydroxy-4-isopropylphenyl)ethyl]benzenesulfonamide.

¹H-NMR (CDCl₃) δ ppm: 1.21 (6H, d, J=7.3 Hz), 2.71–2.86 (3H, m),3.22–3.32 (2H, m), 6.59 (1H, s), 6.72 (1H, d, J=7.6 Hz), 6.89 (1H, d,J=7.6 Hz), 7.02 (1H, d, J=8.5 Hz), 7.59–7.64 (1H, m), 7.85–7.89 (1H, m)

Example 8Ethyl[4-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonyl-amino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate(Compound 19)

A suspension of 149 mg ofethyl[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetatein 1.0 mL of saturated hydrogen chloride ethanol solution was stirred atroom temperature for 3 hours, and the reaction mixture was concentratedunder reduced pressure. To a solution of the residue in 1.0 mL ofethanol was added 206 mg of ammonium acetate, and the mixture wasstirred at room temperature for 13 hours. The reaction mixture wasconcentrated under reduced pressure to give white solid, which wastriturated successively with water, and ethyl acetate-ethanol to give141 mg of ethyl[4-[2-(5-carbamimidoyl-2-hydroxybenzene-sulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]-acetateas a white powder.

¹H-NMR (DMSO-d₆) δ ppm: 1.13 (3H, t, J=7.3 Hz), 2.72 (3H, s), 2.75–2.85(2H, m), 2.90–3.00 (2H, m), 4.09 (2H, q, J=7.3 Hz), 4.76 (2H, s), 6.43(1H, d, J=8.9 Hz), 6.90–6.95 (2H, m), 7.20 (1H, d, J=7.9 Hz), 7.39 (1H,dd, J=7.6, 1.3 Hz), 7.57 (1H, dd, J=8.9, 2.3 Hz), 7.65 (1H, td, J=7.6,1.3 Hz), 7.74 (1H, td, J=7.6, 1.3 Hz), 7.85–8.15 (4H, m), 8.45–8.80 (2H,br)

Example 9Ethyl[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate(Compound 20)

A solution of 16.09 g ofethyl[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetatein 200 mL of 37% hydrogen chloride ethanol solution was stirred at roomtemperature for 4 hours, and the reaction mixture was concentrated underreduced pressure. To a stirred solution of the residue in 180 ml ofethanol was added 27.78 g of ammonium acetate under ice-cooling, and themixture was stirred at room temperature for 18 hours. The reactionmixture was concentrated under reduced pressure, and 10 mL of ethylacetate, 200 mL of water, and 40 mL of hexane were added successively tothe residue. The precipitates were collected by filtration, and washedsuccessively with 1000 mL of water and a mixture of 80 mL of hexane and20 mL of ethyl acetate to give 15.11 g ofethyl[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]acetate.

¹H-NMR (DMSO-d₆) δ ppm: 1.15 (6H, d, J=6.9 Hz), 1.17 (3H, t, J=7.3 Hz),2.65–2.75 (2H, m), 2.75–2.90 (3H, m), 4.13 (2H, q, J=7.3 Hz), 4.75 (2H,s), 6.27 (1H, d, J=9.1 Hz), 6.67 (1H, d, J=1.1 Hz), 6.70–6.85 (2H, m),7.00 (1H, d, J=7.3 Hz), 7.50 (1H, dd, J=9.1, 2.6 Hz), 7.85 (2H, br s),7.95 (1H, d, J=2.6 Hz), 8.47 (1H, br s)

Example 10

The following compounds were prepared according to a similar manner tothat described in Example 8 or 9.

Ethyl[4-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-3′,4′,5′-trifluorobiphenyl-3-yloxy]acetate(Compound 21)

¹H-NMR (DMSO-d₆) δ ppm: 1.18 (3H, t, J=7.3 Hz), 2.77 (2H, t, J=6.9 Hz),2.87 (2H, t, J=6.9 Hz), 4.13 (2H, q, J=7.3 Hz), 4.93 (2H, s), 6.26 (1H,d, J=9.1 Hz), 6.80–6.90 (1H, br s), 7.20–7.30 (3H, m), 7.50 (1H, dd,J=9.1, 2.8 Hz), 7.65–7.75 (2H, m), 7.90–8.35 (4H, m)

Ethyl3-[2-[4-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-3′,4′,5′-trifluorobiphenyl-3-yloxy]acetylamino]propionate(Compound 22)

¹H-NMR (DMSO-d₆) δ ppm: 1.14 (3H, t, J=7.3 Hz), 2.75–2.95 (4H, m), 3.44(2H, q, J=6.0 Hz), 4.02 (2H, q, J=7.3 Hz), 4.62 (2H, s), 6.29 (1H, d,J=9.1 Hz), 6.86 (1H, br s), 7.15–7.30 (3H, m), 7.51 (1H, dd, J=9.1, 2.8Hz), 7.65–7.75 (2H, m), 7.86 (1.5H, br s), 7.96 (1H, d, J=2.8 Hz), 8.12(1H, t, J=6.0 Hz), 8.51 (1.5H, br s)

Methyl4′-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonyl-amino)ethyl]-3′-ethoxycarbonylmethoxybiphenyl-2-carboxylate(Compound 23)

¹H-NMR (DMSO-d₆) δ ppm: 1.17 (3H, t, J=6.9 Hz), 2.77 (2H, t, J=7.3 Hz),2.89 (2H, t, J=7.3 Hz), 3.58 (3H, s), 4.14 (2H, q, J=6.9 Hz), 4.32–4.38(1H, br), 4.78 (2H, s), 6.30 (1H, d, J=9.5 Hz), 6.73 (1H, d, J=1.6 Hz),6.80 (1H, dd, J=7.9, 1.6 Hz), 7.16 (1H, d, J=7.9 Hz), 7.35–7.55 (3H, m),7.59 (1H, td, J=7.9, 1.3 Hz), 7.68 (1H, dd, J=7.9, 1.3 Hz), 7.85 (1.5H,br s), 7.97 (1H, d, J=2.8 Hz), 8.50 (1.5H, br s)

Ethyl[2-[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetylamino]acetate(Compound 24)

¹H-NMR (DMSO-d₆) δ ppm: 1.17 (6H, d, J=7.3 Hz), 1.20 (3H, t, J=7.3 Hz),2.70–2.75 (2H, m), 2.78–2.85 (3H, m), 3.97 (2H, d, J=5.4 Hz), 4.11 (2H,q, J=7.3 Hz), 4.52 (2H, s), 6.27 (1H, d, J=9.1 Hz), 6.75–6.81 (3H, m),7.04 (1H, d, J=8.2 Hz), 7.50 (1H, dd, J=9.1, 2.5 Hz), 7.86 (2H, br s),7.94 (1H, d, J=2.5 Hz), 8.43–8.53(3H, m)

Acetic Acid Salt of2-[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]acetamide(Compound 25)

¹H-NMR (DMSO-d₆) δ ppm: 1.16 (6H, d, J=6.9 Hz), 1.89 (3H, s), 2.68–2.74(2H, m), 2.77–2.84 (3H, m), 4.39 (2H, s), 6.30 (1H, d, J=9.5 Hz), 6.71(1H, d, J=1.3 Hz), 6.76 (1H, dd, J=7.6, 1.3 Hz), 7.02 (1H, d, J=7.6 Hz),7.42–7.48 (3H, m), 7.50 (1H, dd, J=9.5, 2.5 Hz), 7.94 (1H, d, J=2.5 Hz),7.95–8.68 (4H, m)

4-Hydroxy-3-[2-[4-isopropyl-2-(5-oxo-4,5-dihydro[1,3,4]-oxadiazol-2-ylmethoxy)phenyl]ethylsulfamoyl]benzamidinehydrochloride (Compound 26)

¹H-NMR (DMSO-d₆) δ ppm: 1.16 (6H, d, J=6.9 Hz), 2.61–2.67 (2H, m),2.77–2.86 (1H, m), 2.92–3.02 (2H, m), 5.01 (2H, s), 6.77 (1H, dd, J=7.9,1.3 Hz), 6.92 (1H, d, J=1.3 Hz), 6.99 (1H, d, J=7.9 Hz), 7.20 (1H, d,J=8.5 Hz), 7.39 (1H, t, J=6.0 Hz), 7.88 (1H, dd, J=8.5, 2.5 Hz), 8.14(1H, d, J=2.5 Hz), 8.87 (2H, br s), 9.24 (2H, br s), 12.01 (1H, br s),12.51 (1H, br s)

Ethyl4-[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]butyratehydrochloride (Compound 27)

¹H-NMR (DMSO-d₆) δ ppm: 1.16 (6H, d, J=6.6 Hz), 1.17 (3H, t, J=7.3 Hz),1.87–1.95 (2H, m), 2.45 (2H, t, J=7.3 Hz), 2.60–2.66 (2H, m), 2.75–2.85(1H, m), 2.92–3.00 (2H, m), 3.92(2H, t, J=6.3 Hz), 4.06 (2H, q, J=7.3Hz), 6.66–6.71 (1H, m), 6.72–6.76 (1H, m), 6.94 (1H, d, J=7.9 Hz), 7.19(1H, d, J=8.8 Hz), 7.37 (1H, t, J=5.7 Hz), 7.87 (1H, dd, J=8.8, 2.5 Hz),8.15 (1H, d, J=2.5 Hz), 8.86 (2H, br s), 9.25 (2H, br s), 12.01 (1H, brs)

4-Hydroxy-3-[2-(2-hydroxy-4-isopropylphenyl)ethylsulfamoyl]benzamidine(Compound 28)

¹H-NMR (DMSO-d₆) δ ppm: 1.13 (6H, d, J=6.9 Hz), 2.56–2.62 (2H, m),2.66–2.81 (3H, m), 6.27 (1H, d, J=9.1 Hz), 6.56 (1H, dd, J=7.6, 1.6 Hz),6.61 (1H, d, J=1.6 Hz), 6.89 (1H, d, J=7.6 Hz), 7.49 (1H, dd, J=9.1, 2.8Hz), 7.79 (2H, br s), 7.93 (1H, d, J=2.8 Hz), 8.46 (2H, br s)

Ethyl2-[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]propionate(Compound 29)

¹H-NMR (DMSO-d₆) δ ppm: 1.09–1.14 (9H, m), 1.45 (3H, d, J=6.6 Hz),2.61–2.88 (5H, m), 4.09 (2H, q, J=6.9 Hz), 4.88 (1H, q, J=6.6 Hz), 6.27(1H, d, J=9.1 Hz), 6.58 (1H, d, J=1.6 Hz), 6.72 (1H, dd, J=7.9, 1.6 Hz),7.00 (1H, d, J=7.9 Hz), 7.42 (1H, d, J=9.1, 2.8 Hz), 7.93 (1H, d, J=2.8Hz)

2-[2-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]-N,N-dimethylacetamide(Compound 30)

¹H-NMR (DMSO-d₆) δ ppm: 1.15 (6H, d, J=6.9 Hz), 2.62–2.70 (2H, m),2.73–2.85 (6H, m), 2.98 (3H, s), 4.73 (2H, s), 6.26 (1H, d, J=9.5 Hz),6.70–6.74 (2H, m), 6.85 (1H, brs), 6.99 (1H, d, J=8.4 Hz), 7.49 (1H, dd,J=9.5, 3.2 Hz), 7.92 (1H, d, J=3.2 Hz), 8.32 (2H, br s), 8.94 (2H, br s)

4-Hydroxy-3-[2-[4-isopropyl-2-(2-morpholin-4-yl-2-oxoethoxy)phenyl]ethylsulfamoyl]benzamidine(Compound 31)

¹H-NMR (DMSO-d₆) δ ppm: 1.15 (6H, d, J=6.9 Hz), 2.60–2.70 (2H, m),2.73–2.88 (3H, m), 3.39–3.59 (8H, m), 4.31–4.36 (1H, m), 4.76 (2H, s),6.26 (1H, d, J=9.5 Hz), 6.69–6.76 (2H, m), 6.82 (1H, br s), 7.00 (1H, d,J=8.2 Hz), 7.49 (1H, dd, J=9.5, 2.5 Hz), 7.68–8.62 (4H, m)

Acetic Acid Salt ofethyl[4-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-2′-sulfamoylbiphenyl-3-yloxy]-acetate(Compound 32)

¹H-NMR (DMSO-d₆) δ ppm: 1.12 (3H, t, J=7.3 Hz), 1.90 (3H, s), 2.80 (2H,t, J=6.3 Hz), 2.90–3.00 (2H, m), 4.01 (2H, q, J=7.3 Hz), 4.53 (2H, s),6.42 (1H, d, J=9.1 Hz), 6.91(1H, dd, J=7.6, 1.6 Hz), 6.98 (1H, d, J=1.6Hz), 7.15 (1H, d, J=7.6 Hz), 7.30 (1H, dd, J=7.6, 1.3 Hz), 7.50–7.57(2H, m), 7.61 (1H, td, J=7.6, 1.3 Hz), 7.69 (2H, br s), 7.96 (1H, d,J=2.8 Hz), 8.06 (1H, dd, J=7.6, 1.3 Hz),8.10–8.25 (1.5H, br), 8.40–8.60(1.5H, br)

Example 11[4-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-2′-methanesulfonoylbiphenyl-3-yloxy]aceticacid hydrochloride (Compound 33)

To a solution of 290 mg ofethyl[4-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonoylbiphenyl-3-yloxy]acetatein 1.0 mL of acetonitrile was added 0.756 mL of 2 mol/L sodium hydroxidesolution, and the mixture was stirred at room temperature for 30minutes. To the reaction mixture was added 1.26 mL of 2 mol/Lhydrochloric acid, and the mixture was concentrated under reducedpressure. To the residue was added water, and the mixture was purifiedby column chromatography on trimethylaminopropylated silica gel (eluent:10% lmol/L hydrochloric acid-acetonitrile). The eluent was concentratedunder reduced pressure to give 260 mg of[4-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-2′-methanesulfonoylbiphenyl-3-yloxy]aceticacid hydrochloride as a white solid.

¹H-NMR (DMSO-d₆) δ ppm: 2.73 (3H, s), 2.80 (2H, t, J=7.3 Hz), 3.10 (2H,t, J=7.3 Hz), 4.65 (2H, s), 6.85–6.95 (2H, m), 7.16 (1H, d, J=7.6 Hz),7.23 (1H, d, J=8.3 Hz), 7.37(1H, dd, J=7.3, 1.3 Hz), 7.66 (1H, td,J=7.6, 1.3 Hz), 7.75 (1H, td, J=7.6, 1.3 Hz), 7.89 (1H, dd, J=8.3, 2.1Hz) 8.08 (1H, dd, J=7.9, 1.3 Hz), 8.17(1H, d, J=2.1 Hz), 8.91 (2H, brs), 9.28 (2H, br s)

Example 12

The following compounds were prepared according to a similar manner tothat described in Example 11.

[4-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-3′,4′,5′-trifluorobiphenyl-3-yloxy]aceticacid hydrochloride (Compound 34)

¹H-NMR (DMSO-d₆) δ ppm: 2.76 (2H, t, J=7.3 Hz), 3.00–3.15 (2H, m), 4.82(2H, s), 7.10–7.25 (4H, m), 7.35–7.45 (1H, br s), 7.65–7.75 (2H, m),7.87 (1H, dd, J=8.6, 2.1 Hz), 8.14 (1H, d, J=2.1 Hz), 8.89 (2H, br s),9.27 (2H, br s), 11.70–12.40 (1H, br), 12.60–13.30 (1H, br)

3-[2-[4-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-3′,4′,5′-trifluorobiphenyl-3-yloxy]acetylamino]-propionicacid (Compound 35)

¹H-NMR (DMSO-d₆) δ ppm: 2.45 (2H, t, J=6.0 Hz), 2.75–2.90 (4H, m), 3.41(2H, q, J=6.0 Hz), 4.56 (2H, s), 6.55 (1H, d, J=8.8 Hz), 7.20–7.30 (3H,m), 7.61 (1H, dd, J=8.8, 2.8 Hz), 7.70–7.80 (2H, m), 7.89 (1H, t, J=6.0Hz), 8.00 (1H, d, J=2.8 Hz), 8.17 (1.5H, br s), 8.77 (1.5H, br s)

Methyl4′-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-3′-carboxymethoxybiphenyl-2-carboxylatehydrochloride (Compound 36)

¹H-NMR (DMSO-d₆) δ ppm: 2.77 (2H, t, J=7.3 Hz), 3.08 (2H, t, J=7.3 Hz),3.59 (3H, s), 4.64 (2H, s), 6.71 (1H, d, J=1.6 Hz), 6.78 (1H, dd, J=7.6,1.6 Hz), 7.10–7.20 (2H, m), 7.40 (1H, d, J=7.3 Hz), 7.47 (1H, d, J=7.6,1.3 Hz), 7.60 (1H, td, J=7.3, 1.3 Hz), 7.68 (1H, dd, J=7.6, 1.3 Hz),7.86 (1H, dd, J=8.5, 2.2 Hz), 8.15 (1H, d, J=2.2 Hz), 8.82 (2H, br s),9.25 (2H, br s)

[2-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]aceticacid hydrochloride (Compound 37)

¹H-NMR (DMSO-d₆) δ ppm: 1.14 (6H, d, J=6.9 Hz), 2.68 (2H, t, J=7.6 Hz),2.78 (1H, sept, J=6.9 Hz), 2.95–3.05 (2H, m), 4.64 (2H, s), 6.65–6.70(1H, m), 6.72 (1H, dd, J=7.8, 1.2 Hz), 6.97 (1H, d, J=7.8 Hz), 7.25 (1H,d, J=8.4 Hz), 7.30–7.45 (1H, m), 7.90 (1H, dd, J=8.4, 2.8 Hz), 8.15 (1H,dd, J=2.8 Hz), 8.99 (2H, br s),9.29 (2H, s), 12.13 (1H, br s), 12.94(1H, br s)

[2-[2-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]acetylamino]aceticacid (Compound 38)

¹H-NMR (DMSO-d₆) δ ppm: 1.16 (6H, d, J=6.9 Hz), 2.72–2.77 (2H, m),2.78–2.86 (3H, m), 3.79 (2H, d, J=5.7 Hz), 4.47 (2H, s), 6.54 (1H, d,J=9.1 Hz), 6.76 (1H, dd, J=7.6, 1.3 Hz), 6.78–6.79 (1H, m), 7.03 (1H, d,J=7.6 Hz) 7.59 (1H, dd, J=9.1, 2.5 Hz), 7.99 (1H, d, J=2.5 Hz),8.09–8.21 (3H, m), 8.70–8.86 (2H, m)

4-[2-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]butyricacid (Compound 39)

¹H-NMR (DMSO-d₆) δ ppm: 1.15 (6H, d, J=7.3 Hz), 1.85–1.98 (2H, m), 2.42(2H, t, J=7.3 Hz), 2.59–2.69 (2H, m), 2.72–2.86 (3H, m), 3.90 (2H, t,J=6.0 Hz), 6.68 (1H, d, J=7.6 Hz), 6.72 (1H, s.), 6.80 (1H, d, J=8.5Hz), 6.97 (1H, d, J=7.6 Hz), 7.66–7.77 (1H, m), 8.00–8.11 (1H, m), 8.49(2H, br s), 8.93 (2H, br s)

2-[2-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]propionicacid hydrochloride (Compound 40)

¹H-NMR (DMSO-d₆) δ ppm: 1.09–1.16 (6H, m), 1.43 (3H, d, J=6.6 Hz),2.56–2.81 (3H, m), 2.91–3.08 (2H, m), 4.77 (1H, q, J=6.6 Hz), 6.59 (1H,s), 6.70 (1H, d, J=7.9 Hz), 6.96 (1H, d, J=7.9 Hz), 7.23 (1H, d, J=8.8Hz), 7.35 (1H, br s), 7.89 (1H, d, J=8.8, 2.5 Hz), 8.15 (1H, d, J=2.5Hz), 8.96 (2H, br s), 9.28 (2H, br s), 12.12 (1H, br s), 12.95 (1H, brs)

[4-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-2′-sulfamoylbiphenyl-3-yloxy]aceticacid hydrochloride (Compound 41)

¹H-NMR (DMSO-d₆) δ ppm: 2.75–2.85 (2H, m), 3.05–3.15 (2H, m), 4.63 (2H,s), 6.87 (1H, d, J=1.6 Hz), 6.91 (1H, dd, J=7.6, 1.6 Hz), 7.05–7.12 (3H,m), 7.20 (1H, d, J=8.5 Hz), 7.29 (1H, dd, J=7.6, 1.3 Hz), 7.40–7.50 (1H,br s), 7.55 (1H, td, J=7.6, 1.3 Hz), 7.61 (1H, td, J=7.6, 1.3 Hz), 7.88(1H, dd, J=8.5, 2.5 Hz), 8.02 (1H, dd, J=7.6, 1.3 Hz), 8.17 (1H, d,J=2.5 Hz), 8.83 (2H, br s), 9.26 (2H, br s), 12.00 (1H, br s), 12.90(1H, br s)

Example 13[2-[2-(5-Carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]aceticacid (Comopound 42)

Ethyl[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate(50 mg) was dissolved in a mixture of 3 mL of 1 mol/L hydrochloric acidand 1 mL of acetonitrile at 60° C. The solution was stirred at 60° C.for 4 hours, and the colorless solid obtained by concentration underreduced pressure of the reaction mixture was dissolved in a mixture of 3mL of 1 mol/L hydrochloric acid and 1 mL of acetnitrile at 60° C. Afterthe solution was stirred at 60° C. for 4 hours, then at room temperaturefor 10 hours, the reaction mixture was concentrated under reducedpressure to give a colorless solid. The solid was triturated with waterand diethyl ether, and collected by filtration to give 31 mg of[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]aceticacid.

¹H-NMR (DMSO-d₆) δ ppm: 1.15 (6H, d, J=6.9 Hz), 2.61–2.83 (3H, m), 3.05(2H, t, J=7.6 Hz), 4.42 (2H, s), 6.67 (1H, s), 6.69 (1H, d, J=7.5 Hz),6.82 (1H, d, J=9.1 Hz), 6.98(1H, d, J=7.5 Hz), 7.69 (1H, dd, J=9.1, 2.5Hz), 8.05 (1H, d, J=2.5 Hz), 8.56 (2H, br s), 8.94 (2H, br s)

Example 14Ethyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]ethyl]-2′-mthanesulfonylbiphenyl-3-yloxy]acetate(Compound 43)

A suspension of 2.01 g of ethyl[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl-2′-methanesulfonylbiphenyl-3-yloxy]acetatein 1.0 mL of saturated hydrogen chloride ethanol solution was stirred atroom temperature for 3 hours. The reaction mixture was concentratedunder reduced pressure, and the residue was dissolved in 20.0 mL ofethanol. To this solution was added 3.34 g of hydroxylammonium acetate,and the mixture was stirred at room temperature for 13 hours. Thereaction mixture was poured into ethyl acetate-water, and the organiclayer was separated. After the aqueous layer was extracted with ethylacetate, and the organic layers were combined, and washed with brine.The organic layer was dried over anhydrous magnesium sulfate, andfiltered. The filtrate was concentrated under reduced pressure, and theresidue was purified by column chromatography on silica gel (eluent:ethyl acetate) to give 1.90 g of ethyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate,amorphous.

¹H-NMR (DMSO-d₆) δ ppm: 1.12 (3H, t, J=6.9 Hz), 2.70 (3H, s), 2.75–2.85(2, m), 3.00–3.10 (2H, m), 4.08 (2H, q, J=6.9 Hz), 4.75 (2H, s), 5.77(2H, br s), 6.85–6.95 (2H, m), 6.97 (1H, d, J=8.5 Hz), 7.10–7.25 (2H,m), 7.35–7.40 (1H, m) 7.60–7.80 (3H, m), 7.95–8.10 (2H, m), 9.53 (1H, brs), 10.9 (1H, br s)

Example 15

The following compound was prepared according to a similar manner tothat described in Example 14.

Ethyl[2-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]ethyl]-5-isopropylphenoxy]acetate(Compound 44)

¹H-NMR (DMSO-d₆) δ ppm: 1.13 (6H, d, J=6.9 Hz), 1.16 (3H, t, J=7.3 Hz),2.65–2.71 (2H, m), 2.73–2.84 (1H, m), 2.93–3.00 (2H, m), 4.12 (2H, q,J=7.3 Hz), 4.73 (2H, s), 5.77 (2H, br s), 6.65 (1H, d, J=1.3 Hz), 6.72(1H, dd, J=7.9, 1.3 Hz), 6.95 (1H, d, J=8.5 Hz), 6.96 (1H, d, J=7.9 Hz),7.08 (1H, br s), 7.69 (1H, dd, J=8.5, 2.2 Hz), 7.99 (1H, d, J=2.2 Hz),9.53 (1H, br s), 10.85 (1H, br s)

Example 16[4-[2-(5-Cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]aceticacid (Compound 45)

To a stirred solution of 154 g ofethyl[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonyl-biphenyl-3-yloxy]acetatein 1.23 L of ethanol was added 275 mL of 2mol/L sodium hydroxidesolution under ice-cooling, and the mixture was stirred underice-cooling for 1.5 hours. To the reaction mixture was added dropwise275 mL of 2 mol/L hydrochloric acid, and ethanol was removed underreduced pressure. The residue was extracted with ethyl acetate, and theorganic layer was washed with brine. The solvent was dried overanhydrous magnesium sulfate, and removed under reduced pressure to give149 g of[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)-ethyl]-2′-methanesulfonylbiphenyl-3-yloxy)aceticacid.

¹H-NMR (DMSO-d₆) δ ppm: 2.73 (3H, s), 2.75–2.85 (2H, m), 3.05–3.20 (2H,m), 4.66 (2H, s), 6.85–6.95 (2H, m), 7.13 (1H, d, J=8.5 Hz), 7.17 (1H,d, J=7.6 Hz), 7.39 (1H, dd, J=7.5, 1.3 Hz), 7.50–7.60 (1H, m), 7.60–7.70(1H, m), 7.88 (1H, dd, J=8.5, 2.1 Hz), 8.02 (1H, d, J=2.1 Hz), 8.08 (1H,dd, J=8.0, 1.3 Hz), 11.80–12.20 (1H, br), 12.70–13.30 (1H, br)

Example 17Sodium[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)-ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate(Compound 46)

To a stirred solution of 146 g of[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonyl-biphenyl-3-yloxy]aceticacid in 580 mL of ethanol was added 137 mL of 2mol/L sodium hydroxidesolution under ice-cooling, and the solvent was removed under reducedpressure. The residue was suspended with 1.16 L of ethanol, and themixture was stirred under reflux for an hour, then at room temperatureovernight. The obtained white solid was collected by filtration to give129 g ofsodium[4-[2-(5-cyano-2-hydroxybenzenesulfonyl-amino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate.

¹H-NMR (DMSO-d₆) δ ppm: 2.71 (3H, s), 2.75–2.85 (2H, m), 3.10–3.25 (2H,m), 4.39 (2H, s), 6.73 (1H, d, J=8.5 Hz), 6.80–6.90 (2H, m), 7.17 (1H,d, J=8.2 Hz), 7.40 (1H, dd, J=7.6, 1.3 Hz), 7.49 (1H, dd, J=8.8, 2.2Hz), 7.60–7.70 (1H, m), 7.70–7.80 (2H, m), 8.08 (1H, dd, J=8.2, 1.3 Hz)

Example 18[4-[2-[2-Hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonyl-amino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]aceticacid (Compound 47)

Method 1) To a suspension of 79 mg ofethyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]-ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetatein acetonitrile was added 0.401 mL of 1 mol/L sodium hydroxide solution,and the mixture was stirred at room temperature for 30 minutes. To thereaction mixture was added 0.401 mL of 1 mol/L hydrochloric acid, andthe mixture was concentrated under reduced pressure. To the residue wasadded water, and the mixture was purified by column chromatography ontrimethylamino-propylated silica gel (eluent: 10% 1 mol/L hydrochloricacid-acetonitrile). The eluent was concentrated under reduced pressure,and the residue was triturated with ethyl acetate to collect byfiltration of 70 mg of[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]aceticacid as an yellow powder.

Method 2) To a stirred solution of 117 g ofsodium[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetatein 1.17 L of water was added 56 g of 50% aqueous hydroxylamine solutionat room temperature, and the mixture was stirred at 70° C. for 4 hours.To the reaction mixture was added dropwise 1 mol/L hydrochloric acid atroom temperature, and the mixture was stirred at the same temperatureover night. The obtained solid was collected by filtration to give 110 gof[4-[2-[2-hydroxy-5-(N-hydroxy-carbamimidoyl)benzenesulfonylamino]ethyl]-2′-methane-sulfonylbiphenyl-3-yloxy]aceticacid.

¹H-NMR (DMSO-d₆) δ ppm: 2.73 (3H, s), 2.75–2.85 (2H, m), 3.05–3.15 (2H,m), 4.67 (2H, s),6.85–6.95 (2H, m), 7.16 (1H, d, J=7.9 Hz), 7.24 (1H, d,J=8.5 Hz), 7.35–7.50 (2H, m), 7.66 (1H, td, J=7.6, 1.3 Hz), 7.70–7.85(2H, m), 8.00–8.10 (2H, m), 8.45–9.60 (1H, br), 10.80–13.30 (3H, br)

Example 19n-Butyl[4-[2-[2-Hydroxy-5-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetatehydrochloride (Compound 48)

Method 1) A solution of 1.499 g ofethyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]-ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetatein 20 mL of 34% hydrogen chloride n-butanol solution was stirred at 60°C. for 3 hours. After being concentrated under reduced pressure, thereaction mixture was recrystallized from n-butanol-diisopropyl ether togive 1.472 g ofn-butyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetatehydrochloride as a white crystal.

Method 2) A solution of 110 g of[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]aceticacid in 1.00 L of 14% hydrogen chloride n-butanol solution was stirredat 100° C. for 2.5 hours. The reaction mixture was concentrated underreduced pressure, and the residue was washed with ethyl acetate to give111 g of crude crystal. The crude crystal was recrystallized fromn-butanol-diisopropyl ether to give 83.3 g ofn-butyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetatehydrochloride.

¹H-NMR (DMSO-d₆) δ ppm: 0.78 (3H, t, J=7.6 Hz), 1.15–1.30 (2H, m),1.40–1.55 (2H, m), 2.72 (3H, s), 2.75–2.85 (2H, m), 3.05–3.15 (2H, m),4.05 (2H, t, J=6.6 Hz), 4.78 (2H, s), 6.90–6.95 (2H, m), 7.18 (1H, d,J=7.6 Hz), 7.20–7.30 (1H, m), 7.37(1H, d, J=7.6 Hz), 7.42–7.50 (1H, m),7.66 (1H, td, J=7.6, 1.3 Hz), 7.72–7.82 (2H, m), 8.02–8.10 (2H, m),8.60–9.60 (1H, br), 10.85–11.30 (1H, br), 11.80–12.20 (1H, br),12.50–13.05 (1H, br)

Example 20

The following compounds were prepared according to a similar manner tothat described in Example 19.

Cyclohexyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate(Compound 49)

¹H-NMR (CDCl₃) δ ppm: 1.10–1.60 (6H, m), 1.64–1.74 (2H, m), 1.78–1.88(2H, m), 2.66 (3H, s), 2.93 (2H, t, J=6.0 Hz), 3.35 (2H, t, J=6.0 Hz),4.62 (2H, s), 4.82–4.90 (1H, m), 4.95 (2H, s), 5.90–6.05 (1H, br s),6.85–7.00 (3H, m), 7.12 (1H, d, J=7.6 Hz), 7.36 (1H, dd, J=7.9, 1.3 Hz),7.57 (1H, td, J=7.9, 1.3 Hz), 7.62–7.73 (2H, m), 7.96 (1H, d, J=2.2 Hz),8.21 (1H, dd, J=7.9, 1.3 Hz)

Isopropyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate(Compound 50)

¹H-NMR (CDCl₃) δ ppm: 1.26 (6H, d, J=6.3 Hz), 2.65 (3H, s), 2.93 (2H, t,J=6.0 Hz), 3.30–3.40 (2H, m), 4.61 (2H, s), 4.99 (2H, br s), 5.05–5.15(1H, m), 6.04 (1H, br s), 6.85–7.05 (3H, m), 7.12 (1H, d, J=7.6 Hz),7.34–7.45 (1H, m), 7.50–7.80 (3H, m), 7.95–8.00 (1H, m), 8.15–8.30 (1H,m)

Example 21Ethyl[2-[2-[(5-carbamimidoyl-2-hydroxybenzenesulfonyl)-(2-methyl-1,3-thiazole-4-ylmethyl)amino]ethyl]-5-isopropyl-phenoxy]acetate(Compound 51)

A solution of 174 mg ofethyl[2-[2-[(5-cyano-2-hydroxy-benzenesulfonyl)-(2-methyl-1,3-thiazole-4-ylmethyl)amino]-ethyl]-5-isopropylphenoxy]acetatein hydrogen chloride ethanol solution was stirred at room temperaturefor 5 hours. The reaction mixture was concentrated under reducedpressure, and the residue was dissolved in 3 mL of ethanol. To thestirred mixture was added 135 mg of ammonium acetate under ice-cooling,and the mixture was stirred at room temperature for 2 days. To thereaction mixture was added water, and the precipitate was collected byfiltration, and washed with water to give 71 mg ofethyl[2-[2-[(5-carbamimidoyl-2-hydroxybenzenesulfonyl)-(2-methyl-1,3-thiazole-4-ylmethyl)amino]ethyl]-5-isopropyl-phenoxy]acetate.

¹H-NMR (DMSO-d₆) δ ppm: 1.08–1.19 (9H, m), 2.56–2.67 (5H, m), 2.70–2.81(1H, m), 3.25–3.33 (2H, m), 4.11 (2H, q, J=7.3 Hz), 4.63 (2H, s), 4.67(2H, s), 6.22 (1H, d, J=9.1 Hz), 6.62 (1H, s), 6.66–6.72 (1H, m), 6.88(1H, d, J=7.6 Hz), 7.20 (1H, s), 7.45 (1H, dd, J=9.1, 2.8 Hz), 7.54–7.96(2H, br), 8.06 (1H, d, J=2.8 Hz), 8.14–8.67 (2H, br)

Example 22

The following compound was prepared according to a similar manner tothat described in Example 21.

5-Carbamimidoyl-2-hydroxy-N-[2-(4-isopropyl-2-sulfamoylphenyl)ethyl]benzenesulfonamide(Compound 52)

¹H-NMR (DMSO-d₆) δ ppm: 1.20 (6H, d, J=6.9 Hz), 2.87–2.97 (3H, m), 3.07(2H, t, J=7.3 Hz), 6.27 (1H, d, J=9.1 Hz), 7.00–7.65 (5H, m), 7.72 (1H,d, J=1.9 Hz), 7.75–7.90 (2H, br), 7.95 (1H, d, J=2.8 Hz), 8.40–8.60 (2H,m)

Example 23[2-[2-[(5-Carbamimidoyl-2-hydroxybenzenesulfonyl)-(2-methyl-1,3-thiazol-4-ylmethyl)amino]ethyl]-5-isopropylphenoxy]aceticacid (Compound 53)

To a stirred solution of 100 mg of ethyl[2-[2-[(5-carbamimidoyl-2-hydroxybenzenesulfonyl)-(2-methyl-1,3-thiazol-4-ylmethyl)amino]ethyl]-5-isopropylphenoxy]acetatein 0.8 mL of ethanol was added 0.183 mL of 2 mol/L sodium hydroxidesolution under ice-cooling. After being stirred at the same temperaturefor 30 minutes, the reaction mixture was concentrated under reducedpressure. To the stirred solution of the residue in a mixture of 0.8 mLof acetonitrile and 0.8 mL of water was added 0.174 mL of 1 mol/Lhydrochloric acid under ice-cooling, and the mixture was stirred at thesame temperature for 5 minutes. To the mixture was added additional0.174 mL of 1 mol/L hydrochloric acid under ice-cooling, and the mixturewas stirred at the same temperature for 5 minutes. The precipitate wascollected by filtration, and washed with water to give 74 mg of[2-[2-[(5-carbamimidoyl-2-hydroxybenzenesulfonyl)-(2-methyl-1,3-thiazole-4-ylmethyl)amino]ethyl]-5-isopropylphenoxy]aceticacid.

¹H-NMR (DMSO-d₆) δ ppm: 1.15 (6H, d, J=6.9 Hz), 2.62 (3H, s), 2.73–2.84(3H, m), 3.40–3.50 (2H, m), 4.33 (2H, s), 4.53 (2H, s), 6.66 (1H, dd,J=7.6, 1.3 Hz), 6.69 (1H, d, J=1.3 Hz), 6.83 (1H, d, J=7.6 Hz), 6.98(1H, d, J=8.8 Hz), 7.26 (1H, s), 7.72 (1H, dd, J=8.8, 2.5 Hz), 8.12 (1H,d, J=2.5 Hz), 8.48 (2H, br s), 9.14 (2H, br s)

Example 24Amino-[4-hydroxy-3-[[2-[4-isopropyl-2-(ethoxycarbonylmethoxy)phenyl]ethyl]sulfamoyl]phenyl]methylenecarbamoyloxymethyl2,2-dimethylpropionate (Compound 54)

To a stirred solution of 99 mg ofamino-[4-benzyloxy-3-[[2-[4-isopropyl-2-(ethoxycarbonylmethoxy)phenyl]ethyl]-sulfamoyl]phenyl]methylenecarbamoyloxymethyl2,2-dimethylpropionate in 3 mL of tetrahydrofuran was added 9.2 mg of10% palladium on carbon under ice-cooling, and the mixture was stirredunder a hydrogen atmosphere at 30° C. for 1 hour. The insoluble materialwas removed by filtration, and the filtrate was concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (eluent: ethyl acetate-hexane) to give 75 mg ofamino-[4-hydroxy-3-[[2-[4-isopropyl-2-(ethoxycarbonylmethoxy)phenyl]ethyl]sulfamoyl]-phenyl]methylenecarbamoyloxymethyl2,2-dimethylpropionate.

¹H-NMR (CDCl₃) δ ppm: 1.19 (6H, d, J=6.9 Hz), 1.22 (9H, s), 1.35 (3H, t,J=7.3 Hz), 2.73–2.88 (3H, m), 3.20–3.32 (2H, m), 4.32 (2H, q, J=7.3 Hz),4.87 (2H, s), 5.86 (2H, s), 6.11 (1H, br s), 6.52 (1H, s), 6.72 (1H, d,J=7.6 Hz), 6.95 (1H, d, J=7.6 Hz), 7.01 (1H, d, J=8.8 Hz), 8.08–8.15(1H, m), 8.20 (1H, d, J=2.2 Hz), 8.72–9.90 (2H, br)

Example 25

The following compounds were prepared according to a similar manner tothat described in Example 24.

Amino-[4-hydroxy-3-[[2-[4-isopropyl-2-(ethoxycarbonylmethoxy)phenyl]ethyl]sulfamoyl]phenyl]methylenecarbamoyloxymethyl2-acetoxy-2-methylpropionate (Compound 55)

¹H-NMR (CDCl₃) δ ppm: 1.20 (6H, d, J=6.9 Hz), 1.35 (3H, t, J=7.3 Hz),1.57 (6H, s), 2.04 (3H, s), 2.75–2.88 (3H, m), 3.22–3.32 (2H, m), 4.32(2H, q, J=7.3 Hz), 4.69 (2H, s), 5.89 (2H, s), 6.12 (1H, br s),6.51–6.56 (1H, m), 6.73–6.79 (1H, m), 6.95 (1H, d, J=7.9 Hz), 7.01 (1H,d, J=8.8 Hz), 8.11 (1H, dd, J=8.8, 2.2 Hz), 8.21 (1H, d, J=2.2 Hz),8.65–9.95 (2H, m)

Ethyl[4-[2-[5-amino(butoxycarbonylimino)methyl]-2-hydroxybenznesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yl]oxyacetate(Compound 56)

¹H-NMR (DMSO-d₆) δ ppm: 0.90 (3H, t, J=7.3 Hz), 1.11 (3H, t, J=7.3 Hz),1.31–1.40 (2H, m), 1.54–1.63 (2H, m), 2.69 (3H, s), 2.74–2.82 (2H, m),3.02–3.11 (2H, m), 4.00 (2H, t, J=6.6 Hz), 4.05 (2H, q, J=7.3 Hz), 4.74(2H, s), 6.88–6.92 (2H, m), 6.96–7.06 (1H, m), 7.15 (1H, d, J=7.6 Hz),7.19–7.47 (2H, m), 7.65 (1H, td, J=7.6, 0.9 Hz), 7.74 (1H, td, J=7.6,1.3 Hz), 8.00–8.11 (2H, m), 8.39 (1H, d, J=1.9 Hz), 8.85–9.35 (2H, m),11.30–11.70 (1H, br)

Test Example 1 Measurement of Inhibitory Activity for Activated BloodCoagulation Factor X

2.5 μL of a dimethylsulfoxide solution of a test compound, 187.5 μL of100 mM tris-200 mM NaCl buffer (pH 8.4) and 50 μL of 1 mM S-2222(Daiichi Pure Chemicals) aqueous solution were poured into 96 wellmicroplate. Then 10 μL of 0.6 U/mL human activated blood coagulationfactor X (Calbiochem) in gelatin-glycine buffer was added and themixture was incubated for 10 minutes at 37° C. The reaction wasterminated with the addition of 50 μL of 60% acetic acid and absorbance(405 nm) was measured by a microplate reader (SPECTRAmax 250, MolecularDevices).

The group with 2.5 μL of the dimethylsulfoxide solution instead of thetest compound solution was defined as the control, and the group with 10μL of the gelatin-glycine buffer solution instead of human activatedblood coagulation factor X was defined as the blank. The concentrationof a test compound that inhibited the absorbance of control by 50%(IC₅₀) was obtained, and this value was used as the index of inhibitoryactivity for activated blood coagulation factor X. Results were shown asTable 1.

TABLE 1 Inhibitory activity for activated blood Test compound No.coagulation factor X (IC₅₀, μM) Compound 33 0.012 Compound 42 0.10Compound 52 0.016 Compound 53 0.051

Test Example 2 Measurement of Inhibitory Activity for Thrombin

2.5 μL of a dimethylsulfoxide solution of a test compound, 187.5 μL of100 mM tris-200 mM NaCl buffer (pH 8.4) and 50 μL of 1 mM S-2238(Daiichi Pure Chemicals) aqueous solution were poured into 96 wellmicroplate. Then 10 μL of 2.0 U/mL human thrombin (Sigma ChemicalCompany) in gelatin-glycine buffer was added and the mixture wasincubated for 10 minutes at 37° C. The reaction was terminated with theaddition of 50 μL of 60% acetic acid and absorbance (405 nm) wasmeasured by a microplate reader (SPECTRAmax 250, Molecular Devices).

The group with 2.5 μL of the dimethylsulfoxide solution instead of thetest compound solution was defined as the control, and the group with 10μL of the gelatin-glycine buffer solution instead of human thrombin wasdefined as the blank. The concentration of a test compound thatinhibited the absorbance of control by 50% (IC₅₀) was obtained, and thisvalue was used as the index of inhibitory activity for thrombin. Resultswere shown as Table 2.

TABLE 2 Inhibitory activity for thrombin Test compound No. (IC₅₀, μM)Compound 33 >100 Compound 42 >100 Compound 52 >100 Compound 53 >100

Test Example 3 Measurement of Anticoagulation Effects (Prolongation ofPlasma Prothrombin Time)

Two μL of a dimethylsulfoxide solution of a test compound was put in theprocess tube and then incubated at 37° C. One minute after addition of48 μL of normal human plasma (George King Bio-Medical Inc), 100 μL ofplasma prothrombin time reagent (Boehringer Mannheim) prewarmed at 37°C. was added into the mixture. Prothrombin time was measured with acoagulometer (ST4, Boehringer Mannheim).

The group without any test compound was defined as the control. Theconcentration of test compound that prolonged the clotting time of thecontrol by 2 times (CT₂) was obtained and, this value was used as theindex of anticoagulation activity. Results were shown as Table 3.

TABLE 3 Anticoagulation activity Test compound No. (μM) Compound 33 0.52Compound 42 2.4

Test Example 4 Oral Administration Test in Rats

1) Collection of Plasma

Male Wistar rats aged 6–9 weeks (SLC) fasted overnight were used. A testcompound was dissolved or suspended in 0.5% methylcellulose solution atthe concentration of 6.0 mg/mL. Then 5.0 mL/kg of that was orallyadministrated into the rats. Before and at proper time points afteradministration of the test compound, citrated (1:10 dilution, 3.13%sodium citrate) blood was collected from the jugular vein. Plasmasamples were obtained by centrifugation.

2) Measurement of Anti-Activated Blood Coagulation Factor X Activity inPlasma

2.5 μL of plasma sample, 200 μL of 100 mM tris-200 mM NaCl buffer (pH8.4) and 10 μL of 0.06 U/mL human activated blood coagulation factor X(Calbiochem) in gelatin-glycine buffer were poured into 96 wellmicroplate. Then 50 μL of 1 mM S-2222 (Daiichi Pure Chemicals) aqueoussolution was added and the mixture was incubated for 10 minutes at roomtemperature. The reaction was terminated with the addition of 50 μL of60% acetic acid and absorbance (405 nm) was measured by a microplatereader (SPECTRAmax 250, Molecular Devices).

The group with 2.5 μL of the control plasma instead of the plasma samplewas defined as the control, and the group with 10 μL of gelatin-glycinebuffer solution instead of human activated blood coagulation factor Xwas defined as the blank. The inhibitory % of plasma sample wascalculated from absorbance of the control as 100% and this value wasused as the index of anti-activated blood coagulation factor X activityin plasma.

3) Measurement of Prothrombin Time (PT).

Fifty μL of plasma was put in the process tube and then incubated at 37°C. One minute later, 100 μL of plasma PT reagent (Boehringer Mannheim)prewarmed at 37° C. was added into the mixture. PT was measured with acoagulometer (ST4, Boehringer Mannheim).

The ratio of PT at each time point after administration of the testcompound to that of before administration was used as the index ofanticoagulation activity.

4) Results of anti-activated blood coagulation factor X activity inplasma and PT ratio at 30 minutes after oral administration of each testcompound at a dose of 30 mg/kg were shown as Table 4.

TABLE 4 Anti-activated blood coagulation factor X Test compound No.activity in plasma (%) PT ratio Compound 43 32.0 1.31 Compound 48 58.21.50 Compound 49 51.4 1.43

Test Example 5 Acute Toxicity Test

Male ICR mice aged 7 weeks (SLC) were divided into several groupsconsisted of 5 mice. A solution containing a test compound was preparedat the concentration that became the administration volume of the testcompound to be 50.0 mg/10.0 mL/kg. The solution was administered intotail vein at an infusion rate of 1 mL/minute. Observations wereperformed at constant interval, and survival rate was judged for 24hours. Results were shown as Table 5, and no death case was observed.

TABLE 5 Test compound No. Death case Compound 42 0/5

INDUSTRIAL APPLICABILITY

The 5-amidino-2-hydroxybenzenesulfonamide derivatives andpharmaceutically acceptable salts thereof of present inventors show apotent and selective activated blood coagulation factor X inhibitoryactivity. The present invention can provide novel compounds havingexcellent properties as activated blood coagulation factor X inhibitors.In addition, the 5-cyano-2-hydroxybenzenesulfonamide derivativesrepresented by the above general formulae (II) and salts thereof of thepresent invention are important as intermediates in the production ofthe compounds represented by the above general formula (I). Accordingly,the compounds represented by the above general formula (I) of thepresent invention can be readily prepared via these compounds.

1. A 5-amidino-2-hydroxybenzenesulfonamide derivative represented by thegeneral formula:

wherein R¹ represents a hydrogen atom or a lower alkyl group which mayhave a substituent selected from the following group (A); (A) —COOR^(A),—CONR^(B)R^(C), a 3 to 10-membered cycloalkyl group, a 6 to 10-memberedaryl group, a 3 to 10-membered heterocycloalkyl group which may have anoxo group, and a 5 to 10-membered aromatic heterocyclic group which mayhave an oxo group or a lower alkyl group; wherein R^(A) represents ahydrogen atom, a 3 to 10-membered cycloalkyl group or a lower alkylgroup which may have a substituent selected from the following group(i); (i) —COOR^(A1) in which R^(A1) is a hydrogen atom, a 3 to10-membered cycloalkyl group or a lower alkyl group, —OCOR^(A2) in whichR^(A2) is a 3 to 10-membered cycloalkyl group or a lower alkyl group,—OCOOR^(A3) in which R^(A3) is a 3 to 10-membered cycloalkyl group or alower alkyl group, —OR^(A4) in which R^(A4) is a hydrogen atom, a 3 to10-membered cycloalkyl group or a lower alkyl group, —CONR^(A5)R^(A6) inwhich R^(A5) and R^(A6) are independently a hydrogen atom or a loweralkyl group, or —NR^(A5)R^(A6) forms a cyclic amino group, a 3 to10-membered cycloalkyl group, a 6 to 10-membered aryl group, a 3 to10-membered heterocycloalkyl group and a 5 to 10-membered aromaticheterocyclic group; wherein R^(B) and R^(C) independently represent ahydrogen atom or a lower alkyl group which may have a substituentselected from the following group (ii), or —NR^(B)R^(C) forms a cyclicamino group; (ii) —COOR^(B1) in which R^(B1) is a hydrogen atom, a 3 to10-membered cycloalkyl group or a lower alkyl group, —CONR^(B2)R^(C2) inwhich R^(B2) and R^(C2) are independently a hydrogen atom or a loweralkyl group, or —NR^(B2)R^(C2) forms a cyclic amino group, a 3 to10-membered cycloalkyl group, a 6 to 10-membered aryl group, a 3 to10-membered heterocycloalkyl group and a 5 to 10-membered aromaticheterocyclic group; T represents an oxygen atom, a sulfur atom or asulfonyl group; or TR¹ represents —SO₂NR^(B3)R^(C3) in which R^(B3) andR^(C3) are independently a hydrogen atom or a lower alkyl group; R²represents a di(lower alkyl)amino group, a lower alkyl group, a 3 to10-membered cycloalkyl group, a 6 to 10-membered aryl group which mayhave one to three substituents selected from the following group (B), a3 to 10-membered heterocycloalkyl group which may have an oxo group, ora 5 to 10-membered aromatic heterocyclic group which may have asubstituent selected from the following group (C); (B) an oxo group, alower alkyl group, a halo(lower alkyl) group, —Y—R^(D), a halogen atom,a nitro group, an amino group, —COOR^(E), a carbamoyl group, a sulfamoylgroup, a lower alkylsulfonyl group, a mono(lower alkyl)sulfamoyl groupwhich may have —COOR^(F), and a lower alkylsulfonylamino-substituted(lower alkyl) group; wherein Y represents an oxygen atom or a sulfuratom; R^(D) represents a hydrogen atom, a halo(lower alkyl) group or alower alkyl group which may have —COOR^(D1) in which R^(D1) is ahydrogen atom, a 3 to 10-membered cycloalkyl group or a lower alkylgroup; R^(E) represents a hydrogen atom, a 3 to 10-membered cycloalkylgroup or a lower alkyl group; R^(F) represents a hydrogen atom, a 3 to10-membered cycloalkyl group or a lower alkyl group; (C) a lower alkylgroup, an amino group and —COOR^(G); wherein R^(G) represents a hydrogenatom, a 3 to 10-membered cycloalkyl group or a lower alkyl group; Qrepresents a hydrogen atom or a lower alkyl group which may have asubstituent selected from the following group (D); (D) —OR^(H),—COOR^(I), —CONR^(J)R^(K), a 6 to 10-membered aryl group which may haveone to three substituents selected from the following group (iii), and a5 to 10-membered aromatic heterocyclic group which may have one to threesubstituents selected from the following group (iv); wherein R^(H)represents a hydrogen atom or a lower alkyl group which may have—OR^(H1) in which R^(H1) is a hydrogen atom or a lower alkyl group;R^(I) independently has the same meaning as R^(A); R^(J) and R^(K)independently represent a hydrogen atom, a 6 to 10-membered aryl groupwhich may have a carbamoyl group, a 5 to 10-membered aromaticheterocyclic group which may have a substituent selected from thefollowing group (v), or a lower alkyl group which may have a substituentselected from the following group (vi), or —NR^(J)R^(K) forms a cyclicamino group which may have a substituent selected from the followinggroup (vii); (v) a halogen atom, a lower alkyl group, a carbamoyl groupand —COOR^(J1) in which R^(J1) is a hydrogen atom or a lower alkylgroup; (vi) —OR^(J2) in which R^(J2) is a hydrogen atom or a lower alkylgroup, and a 5 to 10-membered aromatic heterocyclic group; (vii) ahydroxy group, a lower alkyl group, a hydroxy(lower alkyl) group, acarbamoyl group, a di(lower alkyl)amino group, a lower acyl group and—COOR^(J3) in which R^(J3) is a hydrogen atom or a lower alkyl group;(iii) a halogen atom, a nitro group, a lower alkyl group, —OR^(L) inwhich R^(L) is a hydrogen atom or a lower alkyl group, and —COOR^(M) inwhich R^(M) is a hydrogen atom or a lower alkyl group; (iv) a halogenatom, an oxo group, a lower alkyl group and a phenyl group; and Zrepresents a hydrogen atom, a hydroxy group or —COOR^(N); wherein R^(N)represents a halo(lower alkyl) group, a 6 to 10-membered aryl group, ora lower alkyl group which may have a substituent selected from thefollowing group (viii); (viii) —OR^(N1) in which R^(N1) is a hydrogenatom or a lower alkyl group, —COOR^(N2) in which R^(N2) is a lower alkylgroup which may have —COOR^(N21) where R^(N21) is a lower alkyl group,—CONR^(N3)R^(N4) in which R^(N3) and R^(N4) are independently a hydrogenatom or a lower alkyl group, or —NR^(N3)R^(N4) forms a cyclic aminogroup, —OCOR^(N5) in which R^(N5) is a lower alkyl group which may have—OCOR^(N51) where R^(N51) is a lower alkyl group, a 3 to 10-memberedheterocycloalkyl group and a 6 to 10-membered aryl group; or apharmaceutically acceptable salt thereof.
 2. A5-amidino-2-hydroxybenzenesulfonamide derivative as claimed in claim 1or a pharmaceutically acceptable salt thereof, wherein Q is a hydrogenatom and Z is not a hydrogen atom.
 3. A5-amidino-2-hydroxybenzenesulfonamide derivative as claimed in claim 2or a pharmaceutically acceptable salt thereof, wherein R is a loweralkyl group having —COOR^(A) wherein R^(A) is a hydrogen atom, a 3 to10-membered cycloalkyl group or a lower alkyl group which may have asubstituent selected from the following group (i); (i) —COOR^(A1) inwhich R^(A1) is a hydrogen atom, a 3 to 10-membered cycloalkyl group ora lower alkyl group, —OCOR^(A2) in which R^(A2) is a 3 to 10-memberedcycloalkyl group or a lower alkyl group, —OCOOR^(A3) in which R^(A3) isa 3 to 10-membered cycloalkyl group or a lower alkyl group, —OR^(A4) inwhich R^(A4) is a hydrogen atom, a 3 to 10-membered cycloalkyl group ora lower alkyl group, —CONR^(A5)R^(A6) in which R^(A5) and R^(A6) areindependently a hydrogen atom or a lower alkyl group, or —NR^(A5)R^(A6)forms a cyclic amino group, a 3 to 10-membered cycloalkyl group, a 6 to10-membered aryl group, a 3 to 10-membered heterocycloalkyl group and a5 to 10-membered aromatic hetero cyclic group; R² is a phenyl grouphaving a substituent selected from the following group (B); (B) an oxogroup, a lower alkyl group, a halo(lower alkyl) group, —Y—R , a halogenatom, a nitro group, an amino group, —COOR^(E), a carbamoyl group, asufamoyl group, a lower alkylsulfonyl group, a mono(loweralkyl)sulfamoyl group which may have —COOR^(F), and a loweralkylsulfonylamino-substituted (lower alkyl) group; wherein Y is anoxygen atom or a sulfur atom; R^(D) is a hydrogen atom, a halo(loweralkyl) group or a lower alkyl group which may have —COOR^(D1) in whichR^(D1) is a hydrogen atom, a 3 to 10-membered cycloalkyl group or alower alkyl group; R^(E) is a hydrogen atom, a 3 to 10-memberedcycloalkyl group or a lower alkyl group; R^(F) is a hydrogen atom, a 3to 10-membered cycloalkyl group or a lower alkyl group; T is an oxygenatom; and Z is a hydroxy group.
 4. A5-amidino-2-hydroxybenzenesulfonamide derivative as claimed in claim 3or a pharmaceutically acceptable salt thereof, wherein R¹ is a methylgroup having —COOR^(A10) wherein R^(A10) is a 3 to 10-memberedcycloalkyl group or a lower alkyl group; and R² is a phenyl group havinga substituent selected from the group consisting of a sufamoyl group, alower alkylsulfonyl group and a mono(lower alkyl)sulfamoyl group.
 5. A5-amidino-2-hydroxybenzenesulfonamide derivative as claimed in claim 1or a pharmaceutically acceptable salt thereof, wherein R¹ is a loweralkyl group having —COOR^(A10) wherein R^(A10) is a 3 to 10-memberedcycloalkyl group or a lower alkyl group; R is a phenyl group having asubstituent selected from the group consisting of a sufamoyl group, alower alkylsulfonyl group and a mono(lower alkyl)sulfamoyl group; Q is ahydrogen atom, T is an oxygen atom; and Z is a hydrogen atom.
 6. The5-amidino-2-hydroxybenzenesulfonamide derivative as claimed in claim 4,represented by the formula:

or a pharmaceutically acceptable salt thereof.
 7. The5-amidino-2-hydroxybenzenesulfonamide derivative as claimed in claim 4,represented by the formula:

or a pharmaceutically acceptable salt thereof.
 8. The5-amidino-2-hydroxybenzenesulfonamide derivative as claimed in claim 4,represented by the formula:

or a pharmaceutically acceptable salt thereof.
 9. The5-amidino-2-hydroxybenzenesulfonamide derivative as claimed in claim 4,represented by the formula:

or a pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising as an active ingredient a5-amidino-2-hydroxybenzenesulfonamide derivative as claimed in claim 1or a pharmaceutically acceptable salt thereof.
 11. A pharmaceuticalcomposition as claimed in claim 10 wherein the composition is anactivated blood coagulation factor X inhibitor.
 12. A pharmaceuticalcomposition as claimed in claim 10 wherein the composition is an agentfor the treatment of a disease requiring inhibition of activated bloodcoagulation factor X.
 13. A method for the manufacture of apharmaceutical composition for the treatment of a disease requiringinhibition of activated blood coagulation factor X which comprisesmixing a 5-amidino-2-hydroxybenzenesulfonamide derivative as claimed inclaim 1 or a pharmaceutically acceptable salt thereof with aconventional pharmaceutical carrier.